Hemostatic devices and methods of use

ABSTRACT

An anchorage device is provided that is configured to surround an implantable medical device. The anchorage device includes a substrate having a hemostatic agent and an active pharmaceutical ingredient selectively positioned on the substrate. Kits, systems and methods are disclosed.

TECHNICAL FIELD

The present disclosure generally relates to anchorage devices andmethods configured for anchoring an implantable medical device within abody, wherein the anchorage device comprises at least one hemostaticagent that is configured to elute over time.

BACKGROUND

Some known anchorage devices may be used to secure an implantablemedical device within a body of a patient. The anchorage device andimplantable medical device can be inserted into a desired locationwithin the body of the patient. The anchorage device can be used to helpanchor or support the implantable medical device to surrounding tissue.Some known anchorage devices are used to provide temporary support totissue during a healing process. For example, some known anchoragedevices can secure one portion of tissue to another portion of tissue.It would be desirable to stop or reduce the flow of blood at a surgicalsite and/or speed up the blood clotting process while anchoring theimplantable medical device to tissue. This disclosure describes animprovement over these prior art technologies.

SUMMARY

New anchorage devices and methods are provided to help anchor or supportan implantable medical device to surrounding tissue. In one embodiment,an anchorage device is provided that includes a substrate having ahemostatic agent (e.g., a hemostatic substrate) and an activepharmaceutical ingredient selectively positioned on the substrate. Inparticular, the active pharmaceutical ingredient is selectivelypositioned on the substrate such that active pharmaceutical ingredientis targeted to a location to treat at least one condition when theanchorage device is implanted within the patient. For example, once alocation within the patient is identified that has a certain condition,such as, for example, infection, scarring and/or infection, a medicalpractitioner may use an anchorage device that has the activepharmaceutical ingredient positioned on the substrate such that theactive pharmaceutical ingredient will be positioned adjacent to thelocation having the condition when the anchorage device is implantedwithin the patient. As such, the active pharmaceutical ingredient willbe able to effectively treat the condition by, for example, providingpain relief, inhibiting scarring or fibrosis and/or inhibiting bacterialgrowth. In some embodiments, the anchorage device is customizable. Thatis, the medical practitioner may be provided with a blank hemostaticsubstrate to which the medical practitioner can selectively apply theactive pharmaceutical ingredient. In particular, the medicalpractitioner can spray the active pharmaceutical ingredient onto thesubstrate at a selected area, coat a selected area of the substrate withthe active pharmaceutical ingredient, coat a selected area of thesubstrate with a material, such as, for example, a polymer to thatincludes the active pharmaceutical ingredient, wash a selected area ofthe substrate with the active pharmaceutical ingredient, or print theactive pharmaceutical ingredient onto a selected area of the substratewith a printer, such as, for example a 3D printer, wherein the selectedarea(s) is an area of the substrate that will be positioned adjacent tothe location within the patient having the condition when the anchoragedevice is implanted within the patient.

In some embodiments, the selected area is all or a portion of a top endof the substrate. In some embodiments, the selected area is all or aportion of a bottom end of the substrate. In some embodiments, theselected area is all or a portion of a side of the substrate. In someembodiments, the selected area is all a portion of one surface of thesubstrate. In some embodiments, the selected area is all or a portion ofa perimeter of the substrate. In some embodiments, the selected area isa combination of a top end of the substrate, a bottom end of thesubstrate, a side of the substrate, a surface of the substrate and/or aperimeter of the substrate, wherein the selected area includes all or aportion of the top end, all or a portion of the bottom end, all or aportion of the side, all a portion the surface and/or all or a portionof the perimeter.

In some embodiments, the active pharmaceutical ingredient is selectivelypositioned on the substrate to define a pattern on the substrate. Insome embodiments, the pattern includes vertical and/or horizontalstripes, wherein the stripes are spaced apart from one another byportions of the substrate that do not include the active pharmaceuticalingredient. In some embodiments, the pattern includes shapes that arearranged in rows and columns. In some embodiments, the shapes are spacedapart from on another by portions of the substrate that do not includethe active pharmaceutical ingredient. In some embodiments, the shapesinclude a circle, an oval, a triangle, a rectangle, a square, a polygonand irregular shapes. Other patterns are also contemplated.

In one embodiment, an anchorage device is provided that includes asubstrate and a hemostatic agent selectively positioned on thesubstrate. In some embodiments, the hemostatic agent is selectivelypositioned on the substrate such that the hemostatic agent is targetedto a location of blood loss in a patient when the anchorage device isimplanted within the patient. In particular, the hemostatic agent isselectively positioned on the substrate such that the hemostatic agentis targeted to a location to prevent or reduce blood loss when theanchorage device is implanted within the patient. For example, once alocation within the patient is identified where blood loss is likely tooccur or is occurring, a medical practitioner may use an anchoragedevice that has the hemostatic agent positioned on the substrate suchthat the hemostatic agent will be positioned adjacent to the locationwhere blood loss is likely to occur or is occurring. As such, thehemostatic agent will be able to effectively prevent, reduce oreliminate blood loss. In some embodiments, the anchorage device iscustomizable. That is, the medical practitioner may be provided with ablank substrate to which the medical practitioner can selectively applythe hemostatic agent. In particular, the medical practitioner can spraythe hemostatic agent onto the substrate at a selected area, coat aselected area of the substrate with the hemostatic agent, coat aselected area of the substrate with a material, such as, for example, apolymer that includes the hemostatic agent, wash a selected area of thesubstrate with the hemostatic agent, or print the hemostatic agent ontoa selected area of the substrate with a printer, such as, for example a3D printer, wherein the selected area(s) is an area of the substratethat will be positioned adjacent to the location within the patientwhere blood loss is occurring or likely to occur when the anchoragedevice is implanted within the patient.

In some embodiments, the selected area is all or a portion of a top endof the substrate. In some embodiments, the selected area is all or aportion of a bottom end of the substrate. In some embodiments, theselected area is all or a portion of a side of the substrate. In someembodiments, the selected area is all a portion of one surface of thesubstrate. In some embodiments, the selected area is all or a portion ofa perimeter of the substrate. In some embodiments, the selected area isa combination of a top end of the substrate, a bottom end of thesubstrate, a side of the substrate, a surface of the substrate and/or aperimeter of the substrate, wherein the selected area includes all or aportion of the top end, all or a portion of the bottom end, all or aportion of the side, all a portion the surface and/or all or a portionof the perimeter.

In some embodiments, the hemostatic agent is selectively positioned onthe substrate to define a pattern on the substrate. In some embodiments,the pattern includes vertical and/or horizontal stripes, wherein thestripes are spaced apart from one another by portions of the substratethat do not include the hemostatic agent. In some embodiments, thepattern includes shapes that are arranged in rows and columns. In someembodiments, the shapes are spaced apart from on another by portions ofthe substrate that do not include the hemostatic agent. In someembodiments, the shapes include a circle, an oval, a triangle, arectangle, a square, a polygon and irregular shapes. Other patterns arealso contemplated.

In some embodiments, the substrate comprises a first piece and a secondpiece that is joined with the first piece. In some embodiments, thefirst and second pieces form an envelope, pouch, or pocket in which, oneside of the envelope, pouch, or pocket includes an opening to allow adevice, such as, for example, the implantable medical device to beinserted through the opening and into a cavity of the envelope, pouch,or pocket. In some embodiments, the substrate is a planar sheet, whichcan be folded or otherwise manipulated to enclose a device, such as, forexample, an implantable medical device within the sheet. In someembodiments, the substrate is a mesh. In some embodiments, the substrateis a thin walled structure, such as, for example, a wafer, sheet ortissue.

Additional features and advantages of various embodiments will be setforth in part in the description that follows, and in part will beapparent from the description, or may be learned by practice of variousembodiments. The objectives and other advantages of various embodimentswill be realized and attained by means of the elements and combinationsparticularly pointed out in the description and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The present disclosure will become more readily apparent from thespecific description accompanied by the following drawings, in which:

FIG. 1 is a side view of one embodiment of an anchorage device inaccordance with the principles of the present disclosure;

FIG. 2 is a side view of one embodiment of the anchorage device shown inFIG. 1 in accordance with the principles of the present disclosure;

FIG. 3 is a side view of one embodiment of the anchorage device shown inFIG. 1 in accordance with the principles of the present disclosure;

FIG. 4 is a side view of one embodiment of the anchorage device shown inFIG. 1 in accordance with the principles of the present disclosure;

FIG. 5 is a side view of one embodiment of the anchorage device shown inFIG. 1 in accordance with the principles of the present disclosure;

FIG. 6 is top, cross sectional view of the anchorage device shown inFIG. 5;

FIG. 7 is a side view of one embodiment of the anchorage device shown inFIG. 1 in accordance with the principles of the present disclosure;

FIG. 8 is a side view of one embodiment of the anchorage device shown inFIG. 1 in accordance with the principles of the present disclosure;

FIG. 9 is a side view of one embodiment of the anchorage device shown inFIG. 1 in accordance with the principles of the present disclosure; and

FIG. 10 is a side view of one embodiment of the anchorage device shownin FIG. 1 in accordance with the principles of the present disclosure;

FIG. 11 is side view of one embodiment of the anchorage device shown inFIG. 1 in accordance with the principles of the present disclosure;

FIG. 12 is a side view of one embodiment of the anchorage device shownin FIG. 1 in accordance with the principles of the present disclosure;

FIG. 13 is a side view of one embodiment of the anchorage device shownin FIG. 1 in accordance with the principles of the present disclosure;

FIG. 14 is a side view of one embodiment of the anchorage device shownin FIG. 1 in accordance with the principles of the present disclosure;

FIG. 15 is a side view of one embodiment of the anchorage device shownin FIG. 1 in accordance with the principles of the present disclosure;

FIG. 16 is top, cross sectional view of the anchorage device shown inFIG. 15;

FIG. 17 is a side view of one embodiment of the anchorage device shownin FIG. 1 in accordance with the principles of the present disclosure;

FIG. 18 is a side view of one embodiment of the anchorage device shownin FIG. 1 in accordance with the principles of the present disclosure;

FIG. 19 is a side view of one embodiment of the anchorage device shownin FIG. 1 in accordance with the principles of the present disclosure;and

FIG. 20 is a side view of one embodiment of the anchorage device shownin FIG. 1 in accordance with the principles of the present disclosure;

FIG. 21 is side view of one embodiment of the anchorage device shown inFIG. 1 in accordance with the principles of the present disclosure;

FIG. 22 is perspective view of one embodiment of the anchorage deviceshown in FIG. 1 in accordance with the principles of the presentdisclosure;

FIG. 23 is perspective view of the anchorage device shown in FIG. 22;

FIG. 24 is side view of the anchorage device shown in FIG. 22;

FIG. 25 is perspective view of one embodiment of the anchorage deviceshown in FIG. 1;

FIG. 26 is perspective end view of the anchorage device shown in FIG.25;

FIG. 27 is a perspective view of an anchorage device in accordance withthe principles of the present disclosure;

FIG. 28 is a depiction of the mechanism of action for a hemostatic agentin accordance with the principles of the present disclosure;

FIG. 29 is a table showing results for Example 2;

FIG. 30 is a perspective view of an anchorage device discussed inExample 9 in accordance with the principles of the present disclosure;

FIG. 31 is a perspective view of an anchorage device discussed inExample 9 in accordance with the principles of the present disclosure;

FIG. 32 is a perspective view of an anchorage device discussed inExample 9 in accordance with the principles of the present disclosure;

FIG. 33 is a perspective view of an anchorage device discussed inExample 9 in accordance with the principles of the present disclosure;

FIG. 34 is a table showing results for Example 13;

FIG. 35 is a graph showing drug content by weight of anchorages devicediscussed in Example 13;

FIG. 36A is a graph showing elution profiles of Samples 1 and 2discussed in Example 13;

FIG. 36B is a graph showing elution profiles of Samples 3 and 4discussed in Example 13;

FIG. 36C is a graph showing elution profiles of Samples 5 and 6discussed in Example 13;

FIG. 36D is a graph showing elution profiles of Samples 9 and 10discussed in Example 13;

FIG. 36E is a graph showing elution profiles of Samples 11 and 12discussed in Example 13;

FIG. 36F is a table showing the expected drug content of Samples 1-6 and9-12 in Example 13;

FIG. 36G is a table showing elution results for Samples 1-6 in Example13;

FIG. 36H is a table showing elution results for Samples 9-12 in Example13;

FIG. 36I is a table showing elution results for Samples 9-12 in Example13;

FIG. 36J is a table showing elution results for Samples 9-12 in Example13;

FIG. 36K is a table showing elution results for Samples 9-12 in Example13;

FIG. 36L includes a graph showing drug release profiles for samplesdiscussed in Example 13;

FIG. 36M includes a graph showing drug release profiles for samplesdiscussed in Example 13;

FIG. 36N includes a graph showing drug release profiles for samplesdiscussed in Example 13;

FIG. 36O includes a graph showing drug release profiles for samplesdiscussed in Example 13;

FIG. 36P includes a graph showing drug release profiles for samplesdiscussed in Example 13;

FIG. 36Q includes a graph showing drug release profiles for samplesdiscussed in Example 13;

FIG. 36R includes a graph showing drug release profiles for samplesdiscussed in Example 13;

FIG. 36S includes a graph showing drug release profiles for samplesdiscussed in Example 13;

FIG. 36T includes a graph showing drug release profiles for samplesdiscussed in Example 13;

FIG. 37 includes graphs showing results discussed in Example 14;

FIG. 38 includes graphs showing results discussed in Example 15;

FIG. 39 is a graph showing results discussed in Example 16;

FIG. 40 is a graph showing results discussed in Example 17;

FIG. 41 is a graph showing results discussed in Example 18;

FIG. 42 includes slides showing results discussed in Example 19; and

FIG. 43 includes images of samples discussed in Example 21;

FIG. 44 is a graph showing results discussed in Example 17.

DETAILED DESCRIPTION

For the purposes of this specification and appended claims, unlessotherwise indicated, all numbers expressing quantities of ingredients,percentages or proportions of materials, and other numerical values usedin the specification and claims, are to be understood as being modifiedin all instances by the term “about.” Accordingly, unless indicated tothe contrary, the numerical parameters set forth in the followingspecification and attached claims are approximations that may varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should at least be construed in light of thenumber of reported significant digits and by applying ordinary roundingtechniques.

Notwithstanding the numerical ranges and parameters set forth herein,the broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Moreover, all ranges disclosed hereinare to be understood to encompass any and all subranges subsumedtherein. For example, a range of “1 to 10” includes any and allsubranges between (and including) the minimum value of 1 and the maximumvalue of 10, that is, any and all subranges having a minimum value ofequal to or greater than 1 and a maximum value of equal to or less than10, e.g., 5.5 to 10.

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingdrawings. While the invention will be described in conjunction with theillustrated embodiments, it will be understood that they are notintended to limit the invention to those embodiments. On the contrary,the invention is intended to cover all alternatives, modifications, andequivalents that may be included within the invention as defined by theappended claims.

This disclosure is directed to anchorage devices, such as, for example,an anchorage device 20. In some embodiments, the components of anchoragedevice 20 can be fabricated from biologically acceptable materialssuitable for medical applications, including metals, synthetic polymers,allografts, xenografts, isografts, ceramics and bone material and/ortheir composites, depending on the particular application and/orpreference of a medical practitioner. For example, the components ofanchorage device 20, individually or collectively, can be fabricatedfrom materials such as stainless steel alloys, commercially puretitanium, titanium alloys, Grade 5 titanium, super-elastic titaniumalloys, cobalt-chrome alloys, stainless steel alloys, superelasticmetallic alloys (e.g., Nitinol, super elasto-plastic metals, such as GUMMETAL® manufactured by Toyota Material Incorporated of Japan), ceramicsand composites thereof such as calcium phosphate (e.g., SKELITE™manufactured by Biologix Inc.), thermoplastics such aspolyaryletherketone (PAEK) including polyetheretherketone (PEEK),polyetherketoneketone (PEKK) and polyetherketone (PEK), carbon-PEEKcomposites, PEEK-BaSO₄ polymeric rubbers, polyethylene terephthalate(PET), fabric, silicone, polyurethane, silicone-polyurethane copolymers,polymeric rubbers, polyolefin rubbers, hydrogels, semi-rigid and rigidmaterials, elastomers, rubbers, thermoplastic elastomers, thermosetelastomers, elastomeric composites, rigid polymers includingpolyphenylene, polyamide, polyimide, polyetherimide, polyethylene,epoxy, tyrosine polyarylate, bone material including autograft,allograft, xenograft or transgenic cortical and/or corticocancellousbone, and tissue growth or differentiation factors, partially resorbablematerials, such as, for example, composites of metals and calcium-basedceramics, composites of PEEK and calcium based ceramics, composites ofPEEK with resorbable polymers, totally resorbable materials, such as,for example, calcium based ceramics such as calcium phosphate,tri-calcium phosphate (TCP), hydroxyapatite (HA)-TCP, calcium sulfate,or other resorbable polymers such as polylactide, polyglycolide,polytyrosine carbonate, polycaroplactone and their combinations.

Various components of anchorage device 20 may have material composites,including the above materials, to achieve various desiredcharacteristics such as strength, rigidity, elasticity, compliance,biomechanical performance, durability and radiolucency or imagingpreference. The components of anchorage device 20, individually orcollectively, may also be fabricated from a heterogeneous material suchas a combination of two or more of the above-described materials. Thecomponents of anchorage device 20 may be monolithically formed,integrally connected or include fastening elements and/or instruments,as described herein.

Substrate

Anchorage device 20 includes a substrate, such as, for example,substrate 22. Substrate 22 is configured to be coupled to and/or appliedto a device, such as, for example, an implantable medical device or anon-implantable medical device, as discussed herein. In someembodiments, substrate 22 is configured to surround and/or enclose atleast a portion of the implantable medical device, as discussed herein.Substrate 22 is configured to be secured to tissue to support theimplantable medical device at a treatment site. Implantable medicaldevices include, for example, vascular devices such as grafts (e.g.,abdominal aortic aneurysm grafts, etc.), stents, catheters (includingarterial, intravenous, blood pressure, stent graft, etc.), valves (e.g.,polymeric or carbon mechanical valves,), embolic protection filters(including distal protection devices), vena cava filters, aneurysmexclusion devices, artificial hearts, cardiac jackets, and heart assistdevices (including left ventricle assist devices), implantabledefibrillators, subcutaneous implantable defibrillators, implantablemonitors, for example, implantable cardiac monitors, electrostimulationdevices and leads (including pacemakers, lead adapters and leadconnectors), implanted medical device power supplies, peripheralcardiovascular devices, atrial septal defect closures, left atrialappendage filters, valve annuloplasty devices, mitral valve repairdevices, vascular intervention devices, ventricular assist pumps, andvascular access devices (including parenteral feeding catheters,vascular access ports, central venous access catheters).

Implantable medical devices may also include, for example, surgicaldevices such as sutures of all types, anastomosis devices (includinganastomotic closures), suture anchors, hemostatic barriers, screws,plates, clips, vascular implants, tissue scaffolds, cerebro-spinal fluidshunts, shunts for hydrocephalus, drainage tubes, catheters includingthoracic cavity suction drainage catheters, abscess drainage catheters,biliary drainage products, and implantable pumps. Implantable medicaldevices may also include, for example, orthopedic devices such as jointimplants, acetabular cups, patellar buttons, bone repair/augmentationdevices, spinal devices (e.g., vertebral disks and the like), bone pins,cartilage repair devices, and artificial tendons. Implantable medicaldevices may also include, for example, dental devices such as dentalimplants and dental fracture repair devices. Implantable medical devicesmay also include, for example, drug delivery devices such as drugdelivery pumps, implanted drug infusion tubes, drug infusion catheters,and intravitreal drug delivery devices. Implantable medical devices mayalso include, for example, ophthalmic devices such as scleral bucklesand sponges, glaucoma drain shunts and intraocular lenses.

Implantable medical devices may also include, for example, urologicaldevices such as penile devices (e.g., impotence implants), sphincter,urethral, prostate, and bladder devices (e.g., incontinence devices,benign prostate hyperplasia management devices, prostate cancerimplants, etc.), urinary catheters including indwelling (“Foley”) andnon-indwelling urinary catheters, and renal devices. Implantable medicaldevices may also include, for example, synthetic prostheses such asbreast prostheses and artificial organs (e.g., pancreas, liver, lungs,heart, etc.). Implantable medical devices may also include, for example,respiratory devices including lung catheters. Implantable medicaldevices may also include, for example, neurological devices such asneurostimulators, neurological catheters, neurovascular ballooncatheters, neuro-aneurysm treatment coils, and neuropatches, splints,ear wicks, ear drainage tubes, tympanostomy vent tubes, otologicalstrips, laryngectomy tubes, esophageal tubes, esophageal stents,laryngeal stents, salivary bypass tubes, and tracheostomy tubes.Implantable medical devices may also include, for example, oncologicalimplants. Implantable medical devices may also include, for example,pain management implants.

In some embodiments, substrate 22 is configured to be coupled to and/orapplied to or to surround and/or enclose at least a portion of anon-implantable medical device, as discussed herein. Non-implantabledevices can include dialysis devices and associated tubing, catheters,membranes, and grafts; autotransfusion devices; vascular and surgicaldevices including atherectomy catheters, angiographic catheters,intraaortic balloon pumps, intracardiac suction devices, blood pumps,blood oxygenator devices (including tubing and membranes), bloodfilters, blood temperature monitors, hemoperfusion units, plasmapheresisunits, transition sheaths, dialators, intrauterine pressure devices,clot extraction catheters, percutaneous transluminal angioplastycatheters, electrophysiology catheters, breathing circuit connectors,stylets (vascular and non-vascular), coronary guide wires, peripheralguide wires; dialators (e.g., urinary, etc.); surgical instruments (e.g.scalpels and the like); endoscopic devices (such as endoscopic surgicaltissue extractors, esophageal stethoscopes); and general medical andmedically related devices including blood storage bags, umbilical tape,membranes, gloves, surgical drapes, wound dressings, wound managementdevices, needles, percutaneous closure devices, transducer protectors,pessary, uterine bleeding patches, PAP brushes, clamps (includingbulldog clamps), cannulae, cell culture devices, materials for in vitrodiagnostics, chromatographic support materials, infection controldevices, colostomy bag attachment devices, birth control devices;disposable temperature probes; and pledgets.

Substrate 22 can have a variety of different configurations, shapes andsizes. For example, substrate 22 can be provided with a size and shapeor other configuration that can provide the functionality of supportingand immobilizing the implantable medical device at a treatment sitewithin a patient's body, while also improving the removability ofanchorage device 20 after the treatment has been completed. In someembodiments, the implantable medical device can be disposed within apocket defined by substrate 22 and anchorage device 20 can be implantedand secured to tissue at a desired treatment site within a body of apatient. As discussed herein, during implantation, scar tissue can format the treatment site and/or tissue can become ingrown within substrate22. After the treatment is completed, the implantable medical device canremain in the patient as discussed below or can be removed from thepatient leaving anchorage device 20 implanted. To remove anchoragedevice 20, tissue that is ingrown within substrate 22 can be cut orotherwise detached from substrate 22. In some embodiments, a portion ofanchorage device 20 may not be removable from the tissue and will remainimplanted within the patient.

Substrate 22 may be formed with one or more biocompatible materials,which may be synthetic or naturally occurring. In some embodiments, theone or more biocompatible materials include, for example, polypropylene,polyester, polytetrafluoroethylene, polyamides, silicones, polysulfones,metals, alloys, titanium, stainless steel, shape memory metals (e.g.Nitinol), and/or combinations thereof.

In some embodiments, substrate 22 is configured to be implantedtemporarily within a body of a patient and/or is configured to beremoved (e.g., explanted) from the patient's body after a period oftime. In such embodiments, substrate 22 may include a non-biodegradablematerial and/or a non-bioresorbable material. For example, substrate 22may be made entirely from a non-biodegradable material and/or anon-bioresorbable material such that substrate 22 is made only from thenon-biodegradable material and/or non-bioresorbable material. In someembodiments, substrate 22 may include one or more non-biodegradableand/or a non-bioresorbable material and one or more biodegradable and/orresorbable material. In some embodiments, one side of substrate 22 mayinclude one or more non-biodegradable and/or a non-bioresorbablematerial and another side of substrate 22 can include one or morebiodegradable and/or resorbable material.

As used herein, the term “biodegradable” refers to, for example, amaterial that can be at least partially broken down or degraded by abodily fluid and discarded as waste from the body and/or a material thatcan be broken down or degraded by a living organism. Thus,“non-biodegradable” can refer to a material that cannot be broken downor degraded by a bodily fluid and/or cannot be broken down or degradedby a living organism. As used herein the term “resorbable” refers to,for example, a material that can be at least partially broken down ordegraded by a bodily fluid and assimilated within the body. Thus, a“non-resorbable” material as used herein can refer to, for example, amaterial that cannot be broken down or degraded by bodily fluid andassimilated within the body.

In some embodiments, the biocompatible biodegradable and/orbioresorbable material or materials may include polymeric and/ornon-polymeric materials, such as, for example, one or more poly(alpha-hydroxy acids), poly (lactide-co-glycolide) (PLGA), polylactide(PLA), poly(L-lactide), polyglycolide (PG), polyethylene glycol (PEG)conjugates of poly (alpha-hydroxy acids), polyorthoesters (POE),polyaspirins, polyphosphazenes, collagen, hydrolyzed collagen, gelatin,hydrolyzed gelatin, fractions of hydrolyzed gelatin, elastin, starch,pre-gelatinized starch, hyaluronic acid, chitosan, alginate, albumin,fibrin, vitamin E analogs, such as alpha tocopheryl acetate, d-alphatocopheryl succinate, D,L-lactide, or L-lactide, -caprolactone,dextrans, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA,PEGT-PBT copolymer (polyactive), methacrylates, poly(N-isopropylacrylamide), PEO-PPO-PEO (pluronics), PEO-PPO-PAAcopolymers, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407,PEG-PLGA-PEG triblock copolymers, POE, SAIB (sucrose acetateisobutyrate), polydioxanone, methylmethacrylate (MMA), MMA andN-vinylpyyrolidone, polyamide, oxycellulose, copolymer of glycolic acidand trimethylene carbonate, polyesteramides, tyrosine polyarylates,polyetheretherketone, polymethylmethacrylate, silicone, hyaluronic acid,chitosan, or combinations thereof. In one embodiment, substrate 22comprises Glycoprene, which is sold by Poly-Med, Inc. As used herein,the term “glycoprene” or “Glycoprene” refers to Glycoprene® orGlycoprene II®. Glycoprene® can refer to different variations of thematerial sold under the trade name Glycoprene®, such as, for example,Glycoprene® 6829, Glycoprene® 8609 and Glycoprene® 7027.

In some embodiments, the biocompatible non-biodegradable and/ornon-bioresorbable material or materials may include polymeric and/ornon-polymeric materials, such as, for example, polyurethane, polyester,polytetrafluoroethylene (PTFE),polyethylacrylate/polymethylmethacrylate, polylactide,polylactide-co-glycolide, polyamides, polydioxanone, polyvinyl chloride,polymeric or silicone rubber, collagen, thermoplastics, or combinationsthereof.

In some embodiments, substrate 22 is configured to be permanentlyimplanted within a body of a patient. In such embodiments, substrate 22may include a biodegradable material and/or a bioresorbable material.For example, substrate 22 may be made entirely from a biodegradablematerial and/or a bioresorbable material such that substrate 22 is madeonly from the biodegradable material and/or bioresorbable material.

In some embodiments, substrate 22 is provided in the form of a mesh, asshown in FIGS. 1-7, 12-17 and 22-26. In some embodiments, the mesh isweb or fabric with a construction of knitted, braided, woven ornon-woven filaments or fibers F that are interlocked in such a way tocreate a fabric or a fabric-like material that includes a matrix offilaments that define multiple pores P. That is, the space betweenadjacent filaments or fibers F define pores P of the mesh. Pores P maybe beneficial to allow tissue in-growth, for example. In someembodiments, apertures may be formed in the mesh by cutting thefilaments or fibers F to decrease the areal density (e.g., surfacedensity) or mass of the mesh and/or further facilitate tissue in-growth.In some embodiments, the apertures that extend through the filaments orfibers F are larger than pores P defined by the filaments or fibers F.

In some embodiments, substrate 22 is provided in the form of a thinwalled structure, such as, for example, a wafer, sheet or tissue, asshown in FIGS. 8-11 and 18-21. In some embodiments, the thin walledstructure does not include any pores or apertures, in contrast to themesh discussed herein. In some embodiments, the thin walled structureincludes pores or apertures that are smaller than the pores or aperturesof the mesh discussed herein. In some embodiments, the thin walledstructure has a thickness that is less than a thickness of the meshdiscussed herein. In some embodiments, the thickness of the thin walledstructure is between about 0.001 inches and about 0.1 inches.

In some embodiments, anchorage device 20 includes an agent, such as, forexample, a hemostatic agent HA that is applied to substrate 22.Hemostatic agent HA can include one or more hemostatic agents, such as,for example, epinephrine, tranexamic acid, chitosan and oxidizedregenerated cellulose. In some embodiments, hemostatic agent HA caninclude one or more of Spongostan®, Surgifoam®, Avitene, thrombin andOstene® in addition to or in place of the hemostatic agents discussedabove. In some embodiments, hemostatic agent HA can include one or moreof protamine, norepinephrine, desmopressin, lysine analogs, collagen,gelatin, polysaccharide spheres, mineral zeolite, bovine thrombin,pooled human thrombin, recombinant thrombin, gelatin and thrombin,collagen and thrombin, cyanacrylate, fibrin glue, polyethylene glycol,and glutaraldehyde in addition to or in place of the hemostatic agentsdiscussed above. In some embodiments, the lysine analog is tranexamicacid and has the formula:

In some embodiments, the anchorage devices disclosed herein utilize oneor more pharmacologic hemostatic agent since pharmacologic hemostaticagents have been found to be desirable over mechanical hemostats for avariety of reasons. Ethnographic research has showed that physiciansdesire a hemostat that can provide an extended elution profile to reducebleeding events for up to 7 days post operatively. Furthermore, there isa possible effect on handling and/or allergic reactions if mechanicalhemostats, such as, for example, oxidized reduced cellulose or chitosanwere used.

In some embodiments, tranexamic acid is preferred for use as hemostaticagent HA. Tranexamic acid is a synthetic analog of the amino acid lysinewith a molecular weight of 157 g/mol. Tranexamic acid is anantifibrinolytic agent that acts by binding to plasminogen and blockingthe interaction of plasminogen with fibrin, therefore preventing thedissolution of a fibrin clot. In the presence of a wound, fibrinolysisoccurs naturally when a lysine residue such as tissue plasminogenactivator (tPA), binds to plasmin causing the clot to lyse (or break).Tranexamic acid blocks tPA and keeps the clot from breaking, thuspreventing unwanted bleeding. FIG. 28 depicts this process.

Prior to a damaged endothelium, tPA is inhibited in the blood byplasminogen activator inhibitor/type 1 (PAI-1). Once damage occurs, thetPA is released slowly into the blood, activating fibrinolysis.Excessive fibrinolysis results in a condition called hyperfibrinolysis,which requires intervention such as fibrinogen, plasma, transfusion orantifibrinolytic therapy, such as tranexamic acid.

Tranexamic acid has been used for over 40 years to reduce bleedingcomplications. Tranexamic acid is most commonly given systemically atdoses of 10 mg/kg followed by infusion of 10 mg/kg/h. Since 2007,tranexamic acid has received widespread approval and clinical use as ahemostatic agent. Knowing that surgical trauma causes fibrinolysis inthe area of the surgical wound itself, topical antifibrinolytic therapyis becoming more common to obtain and maintain hemostasis. Clinicaltrials with topical tranexamic acid use exist for cardiac surgery, CIEDprocedures, orthopedic surgery, spinal surgery, dental extraction andepistaxis, and breast mammoplasty.

To evaluate the efficacy of tranexamic acid, a non-GLP acute porcinestudy was conducted. Doses of 1 mg to 200 mg of tranexamic acid wereused in an in vitro whole blood coagulation test, a hepatic biopsy test,and a subcutaneous ICD surgical procedure.

The in vitro whole blood coagulation test showed no activity fortranexamic acid up to 10 mg/ml. The maximum tranexamic acidconcentration, 200 mg/5 ml, was a slightly higher dose than that usedclinically in a CIED pocket if 50 cc is the assumed blood volume ofinterest. Coagulation time was doubled with this higher dose.

The hepatic biopsy test had a volume of 0.016 ml when the biopsy holewas filled with blood. The minimum tranexamic acid dose evaluated was2.5 mg, which is equivalent to 156 mg/ml. This concentration preventsblood from clotting quickly and these biopsies continued to bleed pastthe endpoint of 10 minutes. This phenomenon is likely due to themultiple bonding sites available to tranexamic acid in whole blood, andthe fact that a biopsy does not induce fibrinolysis.

The subcutaneous surgical site test was conducted with an elevated ACTusing heparin to induce hematoma. Surgical trauma similar to that of aCIEO implant was incurred in each pocket, but some subcutaneous pocketsincurred more trauma than others due to anatomical location. The primaryoutput monitored was accumulated blood as measured by pre-weighed gauze3-hours post-operatively. With only one animal, and two pockets pertreatment, the sample size was too low to show any significance betweenICD only, ICD+polymer, and ICD+polymer+tranexamic acid.

The non-GLP acute porcine study showed that in the dose range evaluated,tranexamic acid has a two-fold increase on clotting time and no effecton reducing bleeding on the hepatic biopsies. In the heparinized ICDpocket procedure, 3.5-22.8 grams of blood accumulated in a 3-hour periodof time regardless of treatment. It appears that subcutaneous pockets inan anticoagulated porcine model would be a translatable model forevaluating efficacy of tranexamic acid because it has a relevant volumeof accumulated blood and surgical trauma similar to that of a CIEDprocedure.

Based upon the non-GLP acute porcine study, tranexamic acidconcentrations of 3.00 mg/L to 30 mg/L are effective in preventingfibrinolysis. As such, in some embodiments, hemostatic agent 24 istranexamic acid and is provided in concentrations of about 3.00 mg/L toabout 30 mg/L. However, it has been found that one tenth of the dosesused in the non-GLP acute porcine study can be effective in reversingfibrinolysis. As such, in some embodiments, hemostatic agent 24 istranexamic acid and is provided in concentrations of about 0.30 mg/L toabout 3.0 mg/L for intravenous applications. In some embodiments,tranexamic acid is provided in concentrations of about 3.78 mg/L toabout 30 mg/L for topical applications as well. However, in someembodiments, however, higher doses of tranexamic acid are used fortopical applications to account for tranexamic acid being widelydistributed throughout the extracellular and intracellular compartmentswhen given preoperatively. Indeed, it has been found that tranexamicacid reaches plasma concentrations in 5-15 minutes. As such, in someembodiments, tranexamic acid is provided in doses of about 1.5 mg toabout 150 mg.

In some embodiments, hemostatic agent HA includes a mixture orcombination of the hemostatic agents discussed herein. In someembodiments, hemostatic agent HA may be applied to substrate 22 byspraying hemostatic agent HA onto substrate 22, coating all or a portionof substrate 22 with hemostatic agent HA, coating all or a portion ofsubstrate 22 with a material, such as, for example, a polymer thatincludes hemostatic agent HA, washing substrate 22 with hemostatic agentHA, or printing hemostatic agent HA on substrate 22 with a printer, suchas, for example a 3D printer. In some embodiments, hemostatic agent HAis applied to fibers F that define the mesh and/or the thin walledstructure of substrate 22.

In some embodiments, hemostatic agent HA entirely coats fibers F whenhemostatic agent HA is applied to substrate 22 such that fibers F areenclosed within hemostatic agent HA. For example, when hemostatic agentHA is applied to substrate 22 via a polymer that includes hemostaticagent HA, the polymer completely coats fibers F such that fibers are notvisible unless and until the polymer degrades or is otherwise removedfrom fibers F. Likewise, hemostatic agent HA may entirely coat fibers Fwhen hemostatic agent HA is applied to substrate 22 by coating substrate22 with hemostatic agent HA. In some embodiments, hemostatic agent HAcovers only a portion of each of fibers F when hemostatic agent HA isapplied to substrate 22 such that other portions of fibers F do includehemostatic agent HA. For example, when hemostatic agent HA is applied tosubstrate 22 via 3D printing, the 3D printer prints hemostatic agent HAonto outer surfaces of fibers F, while opposite inner surfaces of fibersF remain free of hemostatic agent HA. Likewise, hemostatic agent HA maycover only a portion of each of fibers F when hemostatic agent HA isapplied to substrate 22 via spraying. As such, the amount that fibersare covered by hemostatic agent HA can be controlled, at least to somedegree, by the method used to apply hemostatic agent HA to substrate.

In some embodiments, hemostatic agent HA is selectively positioned onsubstrate 22 such that hemostatic agent HA is targeted to a location ofblood loss in a patient when the anchorage device is implanted withinthe patient. In particular, hemostatic agent HA is selectivelypositioned on substrate 22 such that hemostatic agent HA is targeted toa location to prevent or reduce blood loss when the anchorage device isimplanted within the patient. For example, once a location within thepatient is identified where blood loss is likely to occur or isoccurring, a medical practitioner may use anchorage device 20 whereinhemostatic agent HA positioned on substrate 22 such that hemostaticagent HA will be positioned adjacent to the location where blood loss islikely to occur or is occurring. As such, hemostatic agent HA will beable to effectively prevent, reduce or eliminate blood loss. In someembodiments, anchorage device 20 is delivered with hemostatic agent HAalready applied to substrate 22. In some embodiments, anchorage device22 is customizable. That is, the medical practitioner may be providedwith a blank substrate, such as, for example, substrate 22 to which themedical practitioner can selectively apply hemostatic agent HA. Inparticular, the medical practitioner can spray hemostatic agent HA ontosubstrate 22 at a selected area of substrate 22, coat a selected area ofsubstrate 22 with hemostatic agent HA, coat a selected area of substrate22 with a material, such as, for example, a polymer that includeshemostatic agent HA, wash a selected area of substrate 22 withhemostatic agent HA, or print hemostatic agent HA onto a selected areaof substrate 22 with a printer, such as, for example a 3D printer,wherein the selected area(s) is an area of substrate 22 that will bepositioned adjacent to the location within the patient where blood lossis occurring or likely to occur when anchorage device 20 is implantedwithin the patient.

In some embodiments, substrate 22 extends along a longitudinal axis Lbetween a top end 24 and an opposite bottom end 26, as shown in FIG. 2.Top end 24 includes an end surface 24 a and bottom end 26 includes anend surface 26 a. Opposite first and second sides 28, 30 each extendbetween top and bottom ends 24, 26. First side 28 includes a sidesurface 28 a and second side 30 includes a side surface 30 a.Longitudinal axis L is positioned equidistant between side surfaces 28,30. A horizontal midline HML is positioned equidistantly between endsurfaces 24, 26. In some embodiments, end surface 24 a and side surfaces28 a, 30 a are planar and end surface 26 a is convexly curved betweenside surfaces 28 a, 30 a. In some embodiments, end surface 26 a iscontinuously curved from side surface 28 a to side surface 30 a. In someembodiments, end surface 26 a has a continuous radius of curvature fromside surface 28 a to side surface 30 a. In some embodiments, substrateis variously shaped, such as, for example, circular, oval, oblong,triangular, square, rectangular, polygonal, irregular, uniform,non-uniform, offset, staggered, undulating, arcuate, variable and/ortapered.

In some embodiments, hemostatic agent HA is applied to top end 24 ofsubstrate 22. That is, hemostatic agent HA is applied to substrate 22between side surfaces 28, 30 and between end surface 24 and horizontalmidline HML. In some embodiments, hemostatic agent HA is applied fromside surface 28 to side surface 30 and between end surface 24 andhorizontal midline HML. In some embodiments, hemostatic agent HA isapplied from side surface 28 between side surface 30 and from endsurface 24 to horizontal midline HML. In some embodiments, hemostaticagent HA is applied from side surface 28 to side surface 30 and from endsurface 24 to horizontal midline HML. In some embodiments whereinhemostatic agent HA is applied to top end 24 of substrate 22, bottom end26 does not include hemostatic agent HA. That is, substrate 22 is freeof hemostatic agent HA from end surface 26 a to horizontal midline HMLand from side surface 28 a to side surface 30 a.

In some embodiments, hemostatic agent HA is applied to bottom end 26 ofsubstrate 22. That is, hemostatic agent HA is applied to substrate 22between side surfaces 28, 30 and between end surface 26 and horizontalmidline HML. In some embodiments, hemostatic agent HA is applied fromside surface 28 to side surface 30 and between end surface 26 andhorizontal midline HML, as shown in FIG. 2. In at least some of thefigures of this disclosure, hemostatic agent HA is depicted using adarker color or shade than is use to depict substrate 22. That is,hemostatic agent HA is darker than fibers F or other portions ofsubstrate 22 to distinguish hemostatic agent HA from the component orcomponents that make up substrate 22. In some embodiments, hemostaticagent HA is applied between side surface 28 and side surface 30 and fromend surface 26 to horizontal midline HML. In some embodiments,hemostatic agent HA is applied from side surface 28 to side surface 30and from end surface 26 to horizontal midline HML. In some embodimentswherein hemostatic agent HA is applied to bottom end 26 of substrate 22,top end 24 does not include hemostatic agent HA. That is, substrate 22is free of hemostatic agent HA from end surface 24 a to horizontalmidline HML and from side surface 28 a to side surface 30 a.

In some embodiments, hemostatic agent HA is applied to first side 28 ofsubstrate 22. That is, hemostatic agent HA is applied to substrate 22between side surface 28 and longitudinal axis L and between end surface24 and end surface 26. In some embodiments, hemostatic agent HA isapplied from side surface 28 to longitudinal axis L and between endsurface 24 and end surface 26. In some embodiments, hemostatic agent HAis applied between side surface 28 and longitudinal axis L and from endsurface 24 to end surface 26. In some embodiments, hemostatic agent HAis applied from side surface 28 to longitudinal axis L and from endsurface 24 to end surface 26. In some embodiments wherein hemostaticagent HA is applied to first side 28 of substrate 22, second side 30does not include hemostatic agent HA. That is, substrate 22 is free ofhemostatic agent HA from side surface 30 a to longitudinal axis L andfrom end surface 24 to end surface 26.

In some embodiments, hemostatic agent HA is applied to second side 30 ofsubstrate 22. That is, hemostatic agent HA is applied to substrate 22between side surface 30 and longitudinal axis L and between end surface24 and end surface 26. In some embodiments, hemostatic agent HA isapplied from side surface 30 to longitudinal axis L and between endsurface 24 and end surface 26. In some embodiments, hemostatic agent HAis applied between side surface 30 and longitudinal axis L and from endsurface 24 to end surface 26. In some embodiments, hemostatic agent HAis applied from side surface 30 to longitudinal axis L and from endsurface 24 to end surface 26. In some embodiments wherein hemostaticagent HA is applied to second side 30 of substrate 22, first side 28does not include hemostatic agent HA. That is, substrate 22 is free ofhemostatic agent HA from side surface 28 a to longitudinal axis L andfrom end surface 24 to end surface 26.

Substrate 22 includes a first surface, such as, for example, a topsurface 32 that extends from end surface 24 a to end surface 26 a andfrom side surface 28 a to side surface 30 a. Substrate 22 includes asecond surface, such as, for example a bottom surface 34 that isopposite top surface 32. Bottom surface 34 extends from end surface 24 ato end surface 26 a and from side surface 28 a to side surface 30 a. Topand bottom surfaces 32, 34 are best shown in FIGS. 22-24. It isenvisioned that top surface 32 and/or bottom surface can have hemostaticagent HA applied to top end 24 of substrate 22, bottom end 26 ofsubstrate 22, first side 28 of substrate 22 and/or second side 30 ofsubstrate 22. In some embodiments, top surface 32 or bottom surface 34are free of hemostatic agent HA and the other one of top surface 32 andbottom surface 34 have hemostatic agent HA applied to top end 24 ofsubstrate 22, bottom end 26 of substrate 22, first side 28 of substrate22 and/or second side 30 of substrate 22.

Substrate 22 includes a perimeter PR that is defined by end surfaces 24a, 26 a and side surfaces 28 a, 30 a. That is, perimeter PR extendscontinuously from end surface 24 a to side surface 30 a, from sidesurface 30 a to end surface 26 a, from end surface 26 a to side surface28 a and from side surface 28 a to end surface 24 a. In someembodiments, hemostatic agent HA is applied to substrate 22 about all ora portion of perimeter PR, as shown in FIGS. 3-7. In some embodiments,hemostatic agent HA extends inwardly from perimeter PR, as shown in FIG.3. In some embodiments, an interior portion of substrate 22 is free ofhemostatic agent HA. For example, an area of substrate 22 including andsurrounding an intersection of longitudinal axis L and horizontalmidline HML is free of hemostatic agent HA, as shown in FIG. 3.

In some embodiments, hemostatic agent HA extends outwardly fromperimeter PR, as shown in FIG. 4. In some embodiments, the interiorportion of substrate 22 is free of hemostatic agent HA. For example,substrate 22 is free of hemostatic agent HA between end surfaces 24 a,26 a and between side surfaces 28 a, 30 a. In some embodiments,hemostatic agent HA is formed into a structure or body 36 that ispositioned about all or a portion of perimeter PR. That is, body 36includes hemostatic agent HA. In some embodiments, body 36 is made up ofa polymer that includes hemostatic agent HA such that the polymer elutesor releases hemostatic agent HA as the polymer degrades. In someembodiments, body 36 is a cylindrical part that is bent or otherwisemanipulated about all or a portion of perimeter PR. In some embodiments,body 36 is preformed to conform to the shape of perimeter PR. In someembodiments, body 36 is coupled to substrate 22 via one or a pluralityof fasteners 38. In some embodiments, fasteners 38 are loops that arefixed to body 36. In some embodiments, the loops are positioned aroundfibers F that make up substrate 22. In some embodiments, body 36 mayhave various cross section configurations, such as, for example, oval,oblong, triangular, rectangular, square, polygonal, irregular, uniform,non-uniform, variable, tubular and/or tapered. In some embodiments, body36 can be variously connected with substrate 22, such as, for example,monolithic, integral connection, hooks, mutual grooves, barbs and/oradhesive.

In some embodiments, substrate 22 is sealed along at least a portion ofperimeter PR. That is, one or more of end surfaces 24 a, 26 a and sidesurfaces 28 a, 30 a are sealed between or joining top surface 32 withbottom surface 34. For example, in some embodiments, top surface 32 is afirst sheet of substrate 22 and bottom surface 32 of substrate 22wherein the two sheets are joined or sealed together at certain portionsof substrate 22. In some embodiments, substrate 22 includes a weld orseam, such as, for example, a seal 40 that extends within the interiorportion of substrate 22 that seals or otherwise joins top surface 32with bottom surface 34 to form a cavity 42, as shown in FIGS. 5 and 6.In some embodiments, seal 40 and/or cavity 42 extend continuously alongat least one of end surfaces 24 a, 26 a and side surfaces 28 a, 30 a. Asshown in FIG. 5, seal 40 and cavity extend alongside surface 28 acontinuously from end surface 24 a to end surface 26, along end surface26 a from side surface 28 a to side surface 30 a and alongside surface30 a from end surface 26 a to end surface 24 a. Body 36 is positionedwithin cavity 42, as shown in FIG. 5, to couple body 36 to substrate 22.

In some embodiments, body 36 is positioned about perimeter PR such thatbody overlaps and/or covers all or a portion of end surfaces 24 a, 26 aand/or side surfaces 28 a, 30 a, as shown in FIG. 7. As shown in FIG. 7,body 36 extends continuously alongside surface 28 a continuously fromend surface 24 a to end surface 26, along end surface 26 a from sidesurface 28 a to side surface 30 a and alongside surface 30 a from endsurface 26 a to end surface 24 a. Body 36 thus forms an outermostsurface of anchorage device 20.

In some embodiments, hemostatic agent HA is selectively positioned onsubstrate 22 to define a pattern on substrate 22. In some embodiments,the pattern includes vertical and/or horizontal stripes that eachinclude hemostatic agent HA, as shown in FIG. 8. That is, the stripescan extend parallel to longitudinal axis L from end surface 24 a to endsurface 26 a or can extend perpendicular to longitudinal axis L fromside surface 28 a to side surface 30 a. As shown in FIG. 8, the stripesare spaced apart from one another by portions of substrate 22 that donot include hemostatic agent HA. In FIG. 8, the portions of substrate 22that do not include hemostatic agent HA are shown in white. It isenvisioned that substrate 22 can include any number of stripes. In someembodiments, the stripes are formed by applying a material, such as, forexample, masking tape to substrate 22 in areas of substrate 22 wherehemostatic agent is not desired. That is, the masking tape is applied tothe white areas shown in FIG. 8. Substrate 22 is then sprayed, coated,dipped in, or washed with hemostatic agent HA. The masking tape is thenremoved. It is envisioned that the process described herein aboutforming stripes may also be employed to apply hemostatic agent HA tosubstrate to form any of the configurations discussed in thisdisclosure.

In some embodiments, the pattern includes a checkerboard pattern inwhich certain squares of the pattern each include hemostatic agent HAand other squares of the pattern are free of hemostatic agent HA, asshown in FIG. 9. In FIG. 9, the darker squares include hemostatic agentHA and the lighter squares do not include hemostatic agent HA. However,it is envisioned that this may be reversed. In some embodiments, thecheckerboard pattern is formed by applying a material, such as, forexample, masking tape to substrate 22 in areas of substrate 22 wherehemostatic agent is not desired. That is, the masking tape is applied tothe white areas shown in FIG. 9. Substrate 22 is then sprayed, coated,dipped in, or washed with hemostatic agent HA. The masking tape is thenremoved.

In some embodiments, the pattern includes shapes that are arranged inrows and columns, as shown in FIG. 10. The shapes include hemostaticagent HA. In FIG. 10, the shapes are squares. However, it is envisionedthat the shapes can include other shapes, such as, for example, circles,ovals, triangles, rectangles, polygons and irregular shapes. In someembodiments, the shapes are spaced apart from on another by portions ofsubstrate 22 that do not include hemostatic agent HA. That is, substraterows and columns of portions of substrate 22 that do not includehemostatic agent HA space the shapes apart from one another. In FIG. 10,the shapes that include hemostatic agent HA are darker than the portionsof substrate 22 that do not include hemostatic agent HA. In someembodiments, the pattern shown in FIG. 10 is formed by applying amaterial, such as, for example, masking tape to substrate 22 in areas ofsubstrate 22 where hemostatic agent is not desired. That is, the maskingtape is applied to the white areas shown in FIG. 10. Substrate 22 isthen sprayed, coated, dipped in, or washed with hemostatic agent HA. Themasking tape is then removed. In some embodiments, substrate 22 includestwo or more of the patterns shown in FIGS. 8-10, as shown in FIG. 11. Inany of the embodiments discussed above, hemostatic agent HA can alsoinclude one or more of the active pharmaceutical ingredients discussedherein.

In some embodiments, hemostatic agent HA is a material that formssubstrate 22. That is, substrate 22 is a hemostatic substrate that ismade from hemostatic agent HA. For example, fibers F may be made ofhemostatic agent HA or include hemostatic agent HA therein. In someembodiments, hemostatic substrate 22 is made only from hemostatic agentHA. In some embodiments, anchorage device 20 includes an agent, such as,for example, an active pharmaceutical ingredient API that is applied tohemostatic substrate 22.

Active pharmaceutical ingredient API is applied to hemostatic substrate22 to such that anchorage device 20 delivers hemostatic agent HA incombination with active pharmaceutical ingredient API. In someembodiments, active pharmaceutical ingredient 26 is applied directly tohemostatic substrate 22. That is, active pharmaceutical ingredient APIis not applied to hemostatic substrate 22 in a polymer, such as, forexample, a polymer that includes active pharmaceutical ingredient API.In some embodiments, active pharmaceutical ingredient API is applied tohemostatic substrate 22 via a polymer, such as, for example, one of thepolymers discussed herein, wherein the polymer includes activepharmaceutical ingredient API and releases active pharmaceutical agentAPI as the polymer degrades. In some embodiments, active pharmaceuticalingredient API is applied to hemostatic substrate 22 via a polymer thatincludes also includes a hemostatic agent, such as, for example,hemostatic agent HA. In some embodiments, active pharmaceuticalingredient API is applied to hemostatic substrate 22 via a polymer thatdoes not include hemostatic agent HA, such as, for example, a polymerthat is free of hemostatic agent HA.

Active pharmaceutical ingredient API can include one or a combination ofactive pharmaceutical ingredients, such as, for example, anesthetics,antibiotics, anti-inflammatory agents, procoagulant agents,fibrosis-inhibiting agents, anti-scarring agents, antiseptics,leukotriene inhibitors/antagonists, cell growth inhibitors and mixturesthereof. In some embodiments, active pharmaceutical ingredient API is anantibiotic. In some embodiments, the antibiotic is selected from thegroup consisting of rifampin and minocycline and mixtures thereof.

Examples of non-steroidal anti-inflammatories include, but are notlimited to, naproxen, ketoprofen, ibuprofen as well as diclofenac;celecoxib; sulindac; diflunisal; piroxicam; indomethacin; etodolac;meloxicam; r-flurbiprofen; mefenamic; nabumetone; tolmetin, and sodiumsalts of each of the foregoing; ketorolac bromethamine; ketorolacbromethamine tromethamine; choline magnesium trisalicylate; rofecoxib;valdecoxib; lumiracoxib; etoricoxib; aspirin; salicylic acid and itssodium salt; salicylate esters of alpha, beta, gamma-tocopherols andtocotrienols (and all their d, 1, and racemic isomers); and the methyl,ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, esters ofacetylsalicylic acid.

Examples of anesthetics include, but are not limited to, licodaine,bupivacaine, and mepivacaine. Further examples of analgesics,anesthetics and narcotics include, but are not limited to acetaminophen,clonidine, benzodiazepine, the benzodiazepine antagonist flumazenil,lidocaine, tramadol, carbamazepine, meperidine, zaleplon, trimipraminemaleate, buprenorphine, nalbuphine, pentazocain, fentanyl, propoxyphene,hydromorphone, methadone, morphine, levorphanol, and hydrocodone. Localanesthetics have weak antibacterial properties and can play a dual rolein the prevention of acute pain and infection.

Examples of antibacterial agents or antimicrobials include, but are notlimited to, triclosan, chlorohexidine and other cationic biguanides,rifampin, minocycline (or other tetracycline derivatives), vancomycin,gentamycin; gendine; genlenol; genfoctol; clofoctol; cephalosporins andthe like. Further antibacterial agents or antimicrobials includeaztreonam; cefotetan and its disodium salt; loracarbef; cefoxitin andits sodium salt; cefazolin and its sodium salt; cefaclor; ceftibuten andits sodium salt; ceftizoxime; ceftizoxime sodium salt; cefoperazone andits sodium salt; cefuroxime and its sodium salt; cefuroxime axetil;cefprozil; ceftazidime; cefotaxime and its sodium salt; cefadroxil;ceftazidime and its sodium salt; cephalexin; hexachlorophene;cefamandole nafate; cefepime and its hydrochloride, sulfate, andphosphate salt; cefdinir and its sodium salt; ceftriaxone and its sodiumsalt; cefixime and its sodium salt; cetylpyridinium chloride; ofoxacin;linexolid; temafloxacin; fleroxacin; enoxacin; gemifloxacin;lomefloxacin; astreonam; tosufloxacin; clinafloxacin; cefpodoximeproxetil; chloroxylenol; methylene chloride, iodine and iodophores(povidone-iodine); nitrofurazone; meropenem and its sodium salt;imipenem and its sodium salt; cilastatin and its sodium salt;azithromycin; clarithromycin; dirithromycin; erythromycin andhydrochloride, sulfate, or phosphate salts ethylsuccinate, and stearateforms thereof, clindamycin; clindamycin hydrochloride, sulfate, orphosphate salt; lincomycin and hydrochloride, sulfate, or phosphate saltthereof, tobramycin and its hydrochloride, sulfate, or phosphate salt;streptomycin and its hydrochloride, sulfate, or phosphate salt;vancomycin and its hydrochloride, sulfate, or phosphate salt; neomycinand its hydrochloride, sulfate, or phosphate salt; acetyl sulfisoxazole;colistimethate and its sodium salt; quinupristin; dalfopristin;amoxicillin; ampicillin and its sodium salt; clavulanic acid and itssodium or potassium salt; penicillin G; penicillin G benzathine, orprocaine salt; penicillin G sodium or potassium salt; carbenicillin andits disodium or indanyl disodium salt; piperacillin and its sodium salt;α-terpineol; thymol; taurinamides; nitrofurantoin; silver-sulfadiazine;hexetidine; methenamine; aldehydes; azylic acid; silver; benzylperoxide; alcohols; carboxylic acids; salts; nafcillin; ticarcillin andits disodium salt; sulbactam and its sodium salt; methylisothiazolone,moxifloxacin; amifloxacin; pefloxacin; nystatin; carbepenems; lipoicacids and its derivatives; beta-lactams antibiotics; monobactams;aminoglycosides; microlides; lincosamides; glycopeptides; tetracyclines;chloramphenicol; quinolones; fucidines; sulfonamides; macrolides;ciprofloxacin; ofloxacin; levofloxacins; teicoplanin; mupirocin;norfloxacin; sparfloxacin; ketolides; polyenes; azoles; penicillins;echinocandines; nalidixic acid; rifamycins; oxalines; streptogramins;lipopeptides; gatifloxacin; trovafloxacin mesylate; alatrofloxacinmesylate; trimethoprims; sulfamethoxazole; demeclocycline and itshydrochloride, sulfate, or phosphate salt; doxycycline and itshydrochloride, sulfate, or phosphate salt; minocycline and itshydrochloride, sulfate, or phosphate salt; tetracycline and itshydrochloride, sulfate, or phosphate salt; oxytetracycline and itshydrochloride, sulfate, or phosphate salt; chlortetracycline and itshydrochloride, sulfate, or phosphate salt; metronidazole; dapsone;atovaquone; rifabutin; linezolide; polymyxin B and its hydrochloride,sulfate, or phosphate salt; sulfacetamide and its sodium salt; andclarithromycin (and combinations thereof). In some embodiments thepolymer may contain rifampin and another antimicrobial agent, such as,for example, an antimicrobial agent that is a tetracycline derivative.In some embodiments, the polymer contains a cephalosporin and anotherantimicrobial agent. In some embodiments, the polymer containscombinations including rifampin and minocycline, rifampin andgentamycin, and rifampin and minocycline.

When a mixture of two antibiotics is used, they generally present in aratio ranging from about 10:1 to about 1:10. In some embodiments, amixture of rifampin and minocycline are used. In those embodiments, aratio of rifampin to minocycline ranges from about 5:2 to about 2:5. Inother embodiments, the ratio of rifampin to minocycline is about 1:1.

Examples of antifungals include amphotericin B; pyrimethamine;flucytosine; caspofungin acetate; fluconazole; griseofulvin; terbinafineand its hydrochloride, sulfate, or phosphate salt; amorolfine; triazoles(Voriconazole); flutrimazole; cilofungin; LY303366 (echinocandines);pneumocandin; imidazoles; omoconazole; terconazole; fluconazole;amphotericin B, nystatin, natamycin, liposomal amptericin B, liposomalnystatins; griseofulvin; BF-796; MTCH 24; BTG-137586; RMP-7/AmphotericinB; pradimicins; benanomicin; ambisome; ABLC; ABCD; Nikkomycin Z;flucytosine; SCH 56592; ER30346; UK 9746; UK 9751; T 8581; LY121019;ketoconazole; micronazole; clotrimazole; econazole; ciclopirox;naftifine; and itraconazole.

In some embodiments, active pharmaceutical ingredient API includeskeflex, acyclovir, cephradine, malphalen, procaine, ephedrine,adriamycin, daunomycin, plumbagin, atropine, quinine, digoxin,quinidine, biologically active peptides, cephradine, cephalothin,cis-hydroxy-L-proline, melphalan, penicillin V, aspirin, nicotinic acid,chemodeoxycholic acid, chlorambucil, paclitaxel, sirolimus,cyclosporins, 5-fluorouracil and the like.

In some embodiments, active pharmaceutical ingredient API includes oneor more ingredients that act as angiogenensis inhibitors or inhibit cellgrowth such as epidermal growth factor, PDGF, VEGF, FGF (fibroblastgrowth factor) and the like. These ingredients include anti-growthfactor antibodies (neutrophilin-1), growth factor receptor-specificinhibitors such as endostatin and thalidomide. Examples of usefulproteins include cell growth inhibitors such as epidermal growth factor.

Examples of anti-inflammatory compounds include, but are not limited to,anecortive acetate; tetrahydrocortisol, 4,9(11)-pregnadien-17α,21-diol-3,20-dione and its -21-acetate salt; 111-epicortisol;17α-hydroxyprogesterone; tetrahydrocortexolone; cortisona; cortisoneacetate; hydrocortisone; hydrocortisone acetate; fludrocortisone;fludrocortisone acetate; fludrocortisone phosphate; prednisone;prednisolone; prednisolone sodium phosphate; methylprednisolone;methylprednisolone acetate; methylprednisolone, sodium succinate;triamcinolone; triamcinolone-16,21-diacetate; triamcinolone acetonideand its -21-acetate, -21-disodium phosphate, and -21-hemisuccinateforms; triamcinolone benetonide; triamcinolone hexacetonide;fluocinolone and fluocinolone acetate; dexamethasone and its-21-acetate, -21-(3,3-dimethylbutyrate), -21-phosphate disodium salt,-21-diethylaminoacetate, -21-isonicotinate, -21-dipropionate, and-21-palmitate forms; betamethasone and its -21-acetate, -21-adamantoate,-17-benzoate, -17,21-dipropionate, -17-valerate, and -21-phosphatedisodium salts; beclomethasone; beclomethasone dipropionate;diflorasone; diflorasone diacetate; mometasone furoate; andacetazolamide.

Examples of leukotriene inhibitors/antagonists include, but are notlimited to, leukotriene receptor antagonists such as acitazanolast,iralukast, montelukast, pranlukast, verlukast, zafirlukast, andzileuton.

In some embodiments, active pharmaceutical ingredient API includessodium 2-mercaptoethane sulfonate (“MESNA”). MESNA has been shown todiminish myofibroblast formation in animal studies of capsularcontracture with breast implants [Ajmal et al. (2003) Plast. Reconstr.Surg. 112:1455-1461] and may thus act as an anti-fibrosis agent.

Procoagulants include, but are not limited to, zeolites, thrombin, andcoagulation factor concentrates.

In some embodiments, the amount of active pharmaceutical ingredient APIthat is applied to hemostatic substrate 22 ranges between about 0.3 toabout 2.8 micrograms/cm². In other embodiments, the amount of activepharmaceutical ingredient API that is applied to hemostatic substrate 22ranges between about 0.6 to about 1.4 micrograms/cm². In yet otherembodiments, the amount of active pharmaceutical ingredient API that isapplied to hemostatic substrate 22 ranges between about 0.85 to about1.20 micrograms/cm². In yet further embodiments, the amount of activepharmaceutical ingredient API that is applied to hemostatic substrate 22ranges between about 0.90 to about 1.10 micrograms/cm². In yet furtherembodiments, the amount of active pharmaceutical ingredient API that isapplied to hemostatic substrate 22 ranges between about 50 to about 150micrograms/cm². In yet further embodiments, the amount of activepharmaceutical ingredient API that is applied to hemostatic substrate 22ranges between about 62 to about 140 micrograms/cm². In yet furtherembodiments, 62 micrograms/cm² of active pharmaceutical ingredient APIis applied to hemostatic substrate 22. In yet further embodiments, 140micrograms/cm² of active pharmaceutical ingredient API is applied tohemostatic substrate 22.

In other embodiments, active pharmaceutical ingredient API includesrifampin and minocycline and the amount of each of rifampin andminocycline that is applied to hemostatic substrate 22 ranges betweenabout 0.6 to about 1.4 micrograms/cm². In yet other embodiments, theamount of each of rifampin and minocycline that is applied to hemostaticsubstrate 22 ranges between about 0.85 to about 1.20 micrograms/cm². Inyet further embodiments, the amount of each of rifampin and minocyclinethat is applied to hemostatic substrate 22 ranges between about 0.90 toabout 1.10 micrograms/cm².

Active pharmaceutical agent 26 may include any of the activepharmaceutical ingredients discussed herein. Active pharmaceutical agent26 may be incorporated into anchorage device 20 by applying activepharmaceutical ingredient API directly to hemostatic substrate 22 or byapplying active pharmaceutical ingredient API to hemostatic substrate 22via a polymer, such as, for example, one or more of the polymersdiscussed herein. Doses of the active pharmaceutical ingredientsdiscussed herein are known and the amounts of any single activepharmaceutical ingredient to include in anchorage device 20 can readilybe surmised. Any pharmaceutically acceptable form of the activepharmaceutical ingredients discussed herein can be employed in anchoragedevice 20, e.g., the free base or a pharmaceutically acceptable salt orester thereof. Pharmaceutically acceptable salts, for instance, includesulfate, lactate, acetate, stearate, hydrochloride, tartrate, maleate,citrate, phosphate and the like.

In some embodiments, active pharmaceutical ingredient API is applieddirectly to hemostatic substrate 22, as discussed herein. In someembodiments, active pharmaceutical ingredient API may be applied tohemostatic substrate 22 by spraying active pharmaceutical ingredient APIonto hemostatic substrate 22, coating all or a portion of hemostaticsubstrate 22 with active pharmaceutical ingredient API, coating all or aportion of hemostatic substrate 22 with a material, such as, forexample, one or more polymer that includes active pharmaceuticalingredient API, washing hemostatic substrate 22 with activepharmaceutical ingredient API, or printing active pharmaceuticalingredient API on hemostatic substrate 22 with a printer, such as, forexample a 3D printer. In some embodiments, active pharmaceuticalingredient API is a material that forms hemostatic substrate 22. Thatis, hemostatic substrate 22 is made from active pharmaceuticalingredient API and hemostatic agent HA is applied to hemostaticsubstrate 22.

In some embodiments, active pharmaceutical ingredient API includes amixture or combination of the active pharmaceutical ingredientsdiscussed herein. In some embodiments, active pharmaceutical ingredientAPI may be applied to hemostatic substrate 22 by spraying activepharmaceutical ingredient API onto hemostatic substrate 22, coating allor a portion of hemostatic substrate 22 with active pharmaceuticalingredient API, coating all or a portion of hemostatic substrate 22 witha material, such as, for example, a polymer that includes activepharmaceutical ingredient API, washing hemostatic substrate 22 withactive pharmaceutical ingredient API, or printing active pharmaceuticalingredient API on hemostatic substrate 22 with a printer, such as, forexample a 3D printer. In some embodiments, active pharmaceuticalingredient API is applied to fibers F that define the mesh and/or thethin walled structure of hemostatic substrate 22.

In some embodiments, active pharmaceutical ingredient API entirely coatsfibers F when active pharmaceutical ingredient API is applied tohemostatic substrate 22 such that fibers F are enclosed within activepharmaceutical ingredient API. For example, when active pharmaceuticalingredient API is applied to hemostatic substrate 22 via a polymer thatincludes active pharmaceutical ingredient API, the polymer completelycoats fibers F such that fibers are not visible unless and until thepolymer degrades or is otherwise removed from fibers F. Likewise, activepharmaceutical ingredient API may entirely coat fibers F when activepharmaceutical ingredient API is applied to hemostatic substrate 22 bycoating hemostatic substrate 22 with active pharmaceutical ingredientAPI. In some embodiments, active pharmaceutical ingredient API coversonly a portion of each of fibers F when active pharmaceutical ingredientAPI is applied to hemostatic substrate 22 such that other portions offibers F do include active pharmaceutical ingredient API. For example,when active pharmaceutical ingredient API is applied to hemostaticsubstrate 22 via 3D printing, the 3D printer prints activepharmaceutical ingredient API onto outer surfaces of fibers F, whileopposite inner surfaces of fibers F remain free of active pharmaceuticalingredient API. Likewise, active pharmaceutical ingredient API may coveronly a portion of each of fibers F when active pharmaceutical ingredientAPI is applied to hemostatic substrate 22 via spraying. As such, theamount that fibers are covered by active pharmaceutical ingredient APIcan be controlled, at least to some degree, by the method used to applyactive pharmaceutical ingredient API to hemostatic substrate 22.

In some embodiments, active pharmaceutical ingredient API is selectivelypositioned on hemostatic substrate 22 such that active pharmaceuticalingredient API is targeted to a location to treat at least one conditionwhen anchorage device 20 is implanted within the patient. For example,once a location within the patient is identified that has a certaincondition, such as, for example, infection, scarring and/or infection, amedical practitioner may use anchorage device 20 with activepharmaceutical ingredient API positioned on hemostatic substrate 22 suchthat active pharmaceutical ingredient API will be positioned adjacent tothe location having the condition when anchorage device 20 is implantedwithin the patient. As such, active pharmaceutical ingredient API willbe able to effectively treat the condition by, for example, providingpain relief, inhibiting scarring or fibrosis and/or inhibiting bacterialgrowth.

In some embodiments, anchorage device 20 is delivered with activepharmaceutical ingredient API already applied to hemostatic substrate22. In some embodiments, anchorage device 22 is customizable. That is,the medical practitioner may be provided with a blank substrate, suchas, for example, hemostatic substrate 22 to which the medicalpractitioner can selectively apply active pharmaceutical ingredient API.In particular, the medical practitioner can spray active pharmaceuticalingredient API onto hemostatic substrate 22 at a selected area ofhemostatic substrate 22, coat a selected area of hemostatic substrate 22with active pharmaceutical ingredient API, coat a selected area ofhemostatic substrate 22 with a material, such as, for example, a polymerthat includes active pharmaceutical ingredient API, wash a selected areaof hemostatic substrate 22 with active pharmaceutical ingredient API, orprint active pharmaceutical ingredient API onto a selected area ofhemostatic substrate 22 with a printer, such as, for example a 3Dprinter, wherein the selected area(s) is an area of hemostatic substrate22 that will be positioned adjacent to the location within the patientwhere condition exists or is likely to occur when anchorage device 20 isimplanted within the patient.

In some embodiments, active pharmaceutical ingredient API is applied totop end 24 of hemostatic substrate 22. That is, active pharmaceuticalingredient API is applied to hemostatic substrate 22 between sidesurfaces 28, 30 and between end surface 24 and horizontal midline HML.In some embodiments, active pharmaceutical ingredient API is appliedfrom side surface 28 to side surface 30 and between end surface 24 andhorizontal midline HML. In some embodiments, active pharmaceuticalingredient API is applied from side surface 28 between side surface 30and from end surface 24 to horizontal midline HML. In some embodiments,active pharmaceutical ingredient API is applied from side surface 28 toside surface 30 and from end surface 24 to horizontal midline HML. Insome embodiments wherein active pharmaceutical ingredient API is appliedto top end 24 of hemostatic substrate 22, bottom end 26 does not includeactive pharmaceutical ingredient API. That is, hemostatic substrate 22is free of active pharmaceutical ingredient API from end surface 26 a tohorizontal midline HML and from side surface 28 a to side surface 30 a.

In some embodiments, active pharmaceutical ingredient API is applied tobottom end 26 of hemostatic substrate 22. That is, active pharmaceuticalingredient API is applied to hemostatic substrate 22 between sidesurfaces 28, 30 and between end surface 26 and horizontal midline HML.In some embodiments, active pharmaceutical ingredient API is appliedfrom side surface 28 to side surface 30 and between end surface 26 andhorizontal midline HML, as shown in FIG. 12. In at least some of thefigures of this disclosure, active pharmaceutical ingredient API isdepicted using a darker color or shade than is use to depict hemostaticsubstrate 22. That is, active pharmaceutical ingredient API is darkerthan fibers F or other portions of hemostatic substrate 22 todistinguish active pharmaceutical ingredient API from the component orcomponents that make up hemostatic substrate 22. In some embodiments,active pharmaceutical ingredient API is applied between side surface 28and side surface 30 and from end surface 26 to horizontal midline HML.In some embodiments, active pharmaceutical ingredient API is appliedfrom side surface 28 to side surface 30 and from end surface 26 tohorizontal midline HML. In some embodiments wherein activepharmaceutical ingredient API is applied to bottom end 26 of hemostaticsubstrate 22, top end 24 does not include active pharmaceuticalingredient API. That is, hemostatic substrate 22 is free of activepharmaceutical ingredient API from end surface 24 a to horizontalmidline HML and from side surface 28 a to side surface 30 a.

In some embodiments, active pharmaceutical ingredient API is applied tofirst side 28 of hemostatic substrate 22. That is, active pharmaceuticalingredient API is applied to hemostatic substrate 22 between sidesurface 28 and longitudinal axis L and between end surface 24 and endsurface 26. In some embodiments, active pharmaceutical ingredient API isapplied from side surface 28 to longitudinal axis L and between endsurface 24 and end surface 26. In some embodiments, activepharmaceutical ingredient API is applied between side surface 28 andlongitudinal axis L and from end surface 24 to end surface 26. In someembodiments, active pharmaceutical ingredient API is applied from sidesurface 28 to longitudinal axis L and from end surface 24 to end surface26. In some embodiments wherein active pharmaceutical ingredient API isapplied to first side 28 of hemostatic substrate 22, second side 30 doesnot include active pharmaceutical ingredient API. That is, hemostaticsubstrate 22 is free of active pharmaceutical ingredient API from sidesurface 30 a to longitudinal axis L and from end surface 24 to endsurface 26.

In some embodiments, active pharmaceutical ingredient API is applied tosecond side 30 of hemostatic substrate 22. That is, activepharmaceutical ingredient API is applied to hemostatic substrate 22between side surface 30 and longitudinal axis L and between end surface24 and end surface 26. In some embodiments, active pharmaceuticalingredient API is applied from side surface 30 to longitudinal axis Land between end surface 24 and end surface 26. In some embodiments,active pharmaceutical ingredient API is applied between side surface 30and longitudinal axis L and from end surface 24 to end surface 26. Insome embodiments, active pharmaceutical ingredient API is applied fromside surface 30 to longitudinal axis L and from end surface 24 to endsurface 26. In some embodiments wherein active pharmaceutical ingredientAPI is applied to second side 30 of hemostatic substrate 22, first side28 does not include active pharmaceutical ingredient API. That is,hemostatic substrate 22 is free of active pharmaceutical ingredient APIfrom side surface 28 a to longitudinal axis L and from end surface 24 toend surface 26.

It is envisioned that top surface 32 and/or bottom surface can haveactive pharmaceutical ingredient API applied to top end 24 of hemostaticsubstrate 22, bottom end 26 of hemostatic substrate 22, first side 28 ofhemostatic substrate 22 and/or second side 30 of hemostatic substrate22. In some embodiments, top surface 32 or bottom surface 34 are free ofactive pharmaceutical ingredient API and the other one of top surface 32and bottom surface 34 have active pharmaceutical ingredient API appliedto top end 24 of hemostatic substrate 22, bottom end 26 of hemostaticsubstrate 22, first side 28 of hemostatic substrate 22 and/or secondside 30 of hemostatic substrate 22.

In some embodiments, active pharmaceutical ingredient API is applied tohemostatic substrate 22 about all or a portion of perimeter PR, as shownin FIGS. 13-17. In some embodiments, active pharmaceutical ingredientAPI extends inwardly from perimeter PR, as shown in FIG. 13. In someembodiments, an interior portion of hemostatic substrate 22 is free ofactive pharmaceutical ingredient API. For example, an area of hemostaticsubstrate 22 including and surrounding an intersection of longitudinalaxis L and horizontal midline HML is free of active pharmaceuticalingredient API, as shown in FIG. 13.

In some embodiments, active pharmaceutical ingredient API extendsoutwardly from perimeter PR, as shown in FIG. 14. In some embodiments,the interior portion of hemostatic substrate 22 is free of activepharmaceutical ingredient API. For example, hemostatic substrate 22 isfree of active pharmaceutical ingredient API between end surfaces 24 a,26 a and between side surfaces 28 a, 30 a. In some embodiments, activepharmaceutical ingredient API is formed into body 36. That is, body 36includes active pharmaceutical ingredient API. In some embodiments, body36 is made up of a polymer that includes active pharmaceuticalingredient API such that the polymer elutes or releases activepharmaceutical ingredient API as the polymer degrades. In someembodiments, body 36 is a cylindrical part that is bent or otherwisemanipulated about all or a portion of perimeter PR. In some embodiments,body 36 is preformed to conform to the shape of perimeter PR. In someembodiments, body 36 is coupled to hemostatic substrate 22 via one or aplurality of fasteners 38. In some embodiments, fasteners 38 are loopsthat are fixed to body 36. In some embodiments, the loops are positionedaround fibers F that make up hemostatic substrate 22. In someembodiments, body 36 may have various cross section configurations, suchas, for example, oval, oblong, triangular, rectangular, square,polygonal, irregular, uniform, non-uniform, variable, tubular and/ortapered. In some embodiments, body 36 can be variously connected withhemostatic substrate 22, such as, for example, monolithic, integralconnection, hooks, mutual grooves, barbs and/or adhesive.

In some embodiments, hemostatic substrate 22 is sealed along at least aportion of perimeter PR. That is, one or more of end surfaces 24 a, 26 aand side surfaces 28 a, 30 a are sealed between or joining top surface32 with bottom surface 34. For example, in some embodiments, top surface32 is a first sheet of hemostatic substrate 22 and bottom surface 32 ofhemostatic substrate 22 wherein the two sheets are joined or sealedtogether at certain portions of hemostatic substrate 22. In someembodiments, hemostatic substrate 22 includes a weld or seam, such as,for example, a seal 40 that extends within the interior portion ofhemostatic substrate 22 that seals or otherwise joins top surface 32with bottom surface 34 to form a cavity 42, as shown in FIGS. 15 and 16.In some embodiments, seal 40 and/or cavity 42 extend continuously alongat least one of end surfaces 24 a, 26 a and side surfaces 28 a, 30 a. Asshown in FIG. 15, seal 40 and cavity extend alongside surface 28 acontinuously from end surface 24 a to end surface 26, along end surface26 a from side surface 28 a to side surface 30 a and alongside surface30 a from end surface 26 a to end surface 24 a. Body 36 is positionedwithin cavity 42, as shown in FIG. 15, to couple body 36 to hemostaticsubstrate 22.

In some embodiments, body 36 is positioned about perimeter PR such thatbody overlaps and/or covers all or a portion of end surfaces 24 a, 26 aand/or side surfaces 28 a, 30 a, as shown in FIG. 17. As shown in FIG.17, body 36 extends continuously alongside surface 28 a continuouslyfrom end surface 24 a to end surface 26, along end surface 26 a fromside surface 28 a to side surface 30 a and alongside surface 30 a fromend surface 26 a to end surface 24 a. Body 36 thus forms an outermostsurface of anchorage device 20.

In some embodiments, active pharmaceutical ingredient API is selectivelypositioned on hemostatic substrate 22 to define a pattern on hemostaticsubstrate 22. In some embodiments, the pattern includes vertical and/orhorizontal stripes that each include active pharmaceutical ingredientAPI, as shown in FIG. 18. That is, the stripes can extend parallel tolongitudinal axis L from end surface 24 a to end surface 26 a or canextend perpendicular to longitudinal axis L from side surface 28 a toside surface 30 a. As shown in FIG. 18, the stripes are spaced apartfrom one another by portions of hemostatic substrate 22 that do notinclude active pharmaceutical ingredient API. In FIG. 18, the portionsof hemostatic substrate 22 that do not include active pharmaceuticalingredient API are shown in white. It is envisioned that hemostaticsubstrate 22 can include any number of stripes. In some embodiments, thestripes are formed by applying a material, such as, for example, maskingtape to hemostatic substrate 22 in areas of hemostatic substrate 22where hemostatic agent is not desired. That is, the masking tape isapplied to the white areas shown in FIG. 18. Hemostatic substrate 22 isthen sprayed, coated, dipped in, or washed with active pharmaceuticalingredient API. The masking tape is then removed. It is envisioned thatthe process described herein about forming stripes may also be employedto apply active pharmaceutical ingredient API to substrate to form anyof the configurations discussed in this disclosure.

In some embodiments, the pattern includes a checkerboard pattern inwhich certain squares of the pattern each include active pharmaceuticalingredient API and other squares of the pattern are free of activepharmaceutical ingredient API, as shown in FIG. 19. In FIG. 19, thedarker squares include active pharmaceutical ingredient API and thelighter squares do not include active pharmaceutical ingredient API.However, it is envisioned that this may be reversed. In someembodiments, the checkerboard pattern is formed by applying a material,such as, for example, masking tape to hemostatic substrate 22 in areasof hemostatic substrate 22 where hemostatic agent is not desired. Thatis, the masking tape is applied to the white areas shown in FIG. 19.Hemostatic substrate 22 is then sprayed, coated, dipped in, or washedwith active pharmaceutical ingredient API. The masking tape is thenremoved.

In some embodiments, the pattern includes shapes that are arranged inrows and columns, as shown in FIG. 20. The shapes include activepharmaceutical ingredient API. In FIG. 20, the shapes are squares.However, it is envisioned that the shapes can include other shapes, suchas, for example, circles, ovals, triangles, rectangles, polygons andirregular shapes. In some embodiments, the shapes are spaced apart fromon another by portions of hemostatic substrate 22 that do not includeactive pharmaceutical ingredient API. That is, substrate rows andcolumns of portions of hemostatic substrate 22 that do not includeactive pharmaceutical ingredient API space the shapes apart from oneanother. In FIG. 20, the shapes that include active pharmaceuticalingredient API are darker than the portions of hemostatic substrate 22that do not include active pharmaceutical ingredient API. In someembodiments, the pattern shown in FIG. 20 is formed by applying amaterial, such as, for example, masking tape to hemostatic substrate 22in areas of hemostatic substrate 22 where hemostatic agent is notdesired. That is, the masking tape is applied to the white areas shownin FIG. 20. Hemostatic substrate 22 is then sprayed, coated, dipped in,or washed with active pharmaceutical ingredient API. The masking tape isthen removed. In some embodiments, hemostatic substrate 22 includes twoor more of the patterns shown in FIGS. 18-20, as shown in FIG. 21.

The polymer discussed herein, such as, for example, the polymer thatcontains hemostatic agent HA or active pharmaceutical ingredient API isselected from the group consisting of polylactic acid, polyglycolicacid, poly(L-lactide), poly(D,L-lactide)polyglycolicacid[polyglycolide], poly(L-lactide-co-D,L-lactide),poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide),poly(glycolide-co-trimethylene carbonate),poly(D,L-lactide-co-caprolactone), poly(glycolide-co-caprolactone),polyethylene oxide, polydioxanone, polypropylene fumarate, poly(ethylglutamate-co-glutamic acid), poly(tert-butyloxy-carbonylmethylglutamate), polycaprolactone, polycaprolactone co-butylacrylate,polyhydroxybutyrate, copolymers of polyhydroxybutyrate,poly(phosphazene), poly(phosphate ester), poly(amino acid),polydepsipeptides, maleic anhydride copolymers, polyiminocarbonates,poly[(97.5% dimethyl-trimethylene carbonate)-co-(2.5% trimethylenecarbonate)], poly(orthoesters), tyrosine-derived polyarylates,tyrosine-derived polycarbonates, tyrosine-derived polyiminocarbonates,tyrosine-derived polyphosphonates, polyethylene oxide, polyethyleneglycol, polyalkylene oxides, hydroxypropylmethylcellulose,polysaccharides such as hyaluronic acid, chitosan and regeneratecellulose. In some embodiments, the polymer may include combinations,blends or mixtures of the polymers discussed herein. In someembodiments, the polymer includes hemostatic agent HA and activepharmaceutical ingredient API. In some embodiments, wherein hemostaticagent HA or active pharmaceutical ingredient API is applied to substrate22, both hemostatic agent HA and active pharmaceutical ingredient APIcan be applied to substrate 22. Hemostatic agent HA and activepharmaceutical ingredient API can be applied to substrate 22 in themanners discussed herein that discuss applying hemostatic agent HA oractive pharmaceutical ingredient API to substrate 22.

In some embodiments, the polymer is a polyarylate. In some embodiments,the polymer is a tyrosine-derived polyarylate. In some embodiments, thetyrosine-derived polyarylate is p(DTE co X % DT succinate), where X isabout 10% to about 30%. In some embodiments, the tyrosine-derivedpolyarylate is p(DTE co X % DT succinate), where X ranges from about26.5% to about 28.5%. In some embodiments, the tyrosine-derivedpolyarylate is p(DTE co X % DT succinate), where X is about 27.5%. Insome embodiments, the polymer is P22-27.5 DT.

As used herein, DTE is the diphenol monomer desaminotyrosyl-tyrosineethyl ester; DTBn is the diphenol monomer desaminotyrosyl-tyrosinebenzyl ester; DT is the corresponding free acid form, namelydesaminotyrosyl-tyrosine. BTE is the diphenol monomer 4-hydroxy benzoicacid-tyrosyl ethyl ester; BT is the corresponding free acid form, namely4-hydroxy benzoic acid-tyrosine.

P22-XX is a polyarylate copolymer produced by condensation of DTE andDTBn with succinic acid followed by removal of benzyl group. P22-10,P22-15, P22-20, P22-XX, etc., represents copolymers different percentageof DT (i.e., 10, 15, 20 and % DT, etc.) In some embodiments, the polymeris produced by condensation of DTBn with succinic acid followed byremoval of benzyl group. This polymer is represented as P02-100.

In some embodiments, the polymer includes one or more polyarylates thatare copolymers of desaminotyrosyl-tyrosine (DT) and andesaminotyrosyl-tyrosyl ester (DT ester), wherein the copolymercomprises from about 0.001% DT to about 80% DT and the ester moiety canbe a branched or unbranched alkyl, alkylaryl, or alkylene ether grouphaving up to 18 carbon atoms, any group of which can, optionally have apolyalkylene oxide therein. Similarly, another group of polyarylates arethe same as the foregoing but the desaminotyrosyl moiety is replaced bya 4-hydroxybenzoyl moiety. In some embodiments, the DT or BT contentsinclude those copolymers with from about 1% to about 30%, from about 5%to about 30% from about 10 to about 30% DT or BT. In some embodiments,the diacids (used informing the polyarylates) include succinate,glutarate and glycolic acid.

In some embodiments, the polymer includes one or more biodegradable,resorbable polyarylates and polycarbonates. These polymers, include, butare not limited to, BTE glutarate, DTM glutarate, DT propylamideglutarate, DT glycineamide glutarate, BTE succinate, BTM succinate, BTEsuccinate PEG, BTM succinate PEG, DTM succinate PEG, DTM succinate, DTN-hydroxysuccinimide succinate, DT glucosamine succinate, DT glucosamineglutarate, DT PEG ester succinate, DT PEG amide succinate, DT PEG esterglutarate, DT PEG ester succinate, DTMB P(Desaminotyrsoyl tyrosinemethylparaben ester-glutarate), and DTPP P(Desaminotyrsoyl tyrosinepropylparaben ester-glutarate).

In some embodiments, the polymer is one more polymers from the DTE-DTsuccinate family of polymers, e.g., the P22-xx family of polymers havingfrom 0-50%, 5-50%, 5-40%, 1-30% or 10-30% DT, including but not limitedto, about 1, 2, 5, 10, 15, 20, 25, 27.5, 30, 35, 40%, 45% and 50% DT. Insome embodiments, the polymer is P22-27.5 DT.

In some embodiments, the polymer has diphenol monomer units that arecopolymerized with an appropriate chemical moiety to form a polyarylate,a polycarbonate, a polyiminocarbonate, a polyphosphonate or any otherpolymer.

In some embodiments, the polymer is tyrosine-based polyarylate. In someembodiments, the polymer includes blends and copolymers withpolyalkylene oxides, including polyethylene glycol (PEG).

In some embodiments, the polymer can have from 0.1-99.9% PEG diacid topromote the degradation process. In some embodiments, the polymerincludes blends of polyarylates or other biodegradable polymers withpolyarylates.

The polymer is configured to release hemostatic agent hemostatic agentHA or active pharmaceutical ingredient API over time, as discussedherein. In some embodiments, the polymer is configured to releasehemostatic agent HA or active pharmaceutical ingredient API over a timeperiod ranging from about 1 hour to about 168 hours. In someembodiments, the polymer is configured to release hemostatic agent HA oractive pharmaceutical ingredient API over a time period ranging from 1hour to 72 hours. In some embodiments, the polymer is configured torelease hemostatic agent HA or active pharmaceutical ingredient API overa time period ranging from 1 hour to 24 hours.

In some embodiments, the polymer is configured to release hemostaticagent HA or active pharmaceutical ingredient API over time in an areasurrounding or adjacent to anchorage device 20 (such as, for example,within the device “pocket” or within 3 inches in all dimensions). Insome embodiments, the polymer is configured to release hemostatic agentHA or active pharmaceutical ingredient API for up to 30 hours. In someembodiments, the polymer is configured to release between about 40% andabout 100% of hemostatic agent HA or active pharmaceutical ingredientAPI over a period of at least about 30 hours. In some embodiments, thepolymer is configured to release 60% and about 100% of hemostatic agentHA or active pharmaceutical ingredient API over a period of at leastabout 30 hours. In some embodiments, the polymer is configured torelease between about 65% and about 100% of hemostatic agent HA oractive pharmaceutical ingredient API over a period of at least about 36hours. In some embodiments, the polymer is configured to release 80% andabout 100% of hemostatic agent HA or active pharmaceutical ingredientAPI over a period of at least about 36 hours. In some embodiments, thepolymer is configured to release between about 60% and about 100% ofhemostatic agent HA or active pharmaceutical ingredient API over aperiod of at least about 48 hours. In some embodiments, the polymer isconfigured to release 80% and about 100% of hemostatic agent HA oractive pharmaceutical ingredient API over a period of at least about 48hours. In some embodiments, the polymer is configured to release betweenabout 60% and about 100% of hemostatic agent HA or active pharmaceuticalingredient API over a period of at least about 60 hours. In someembodiments, the polymer is configured to release 80% and about 100% ofhemostatic agent HA or active pharmaceutical ingredient API over aperiod of at least about 60 hours. In some embodiments, the polymer isconfigured to release 80% and about 100% of hemostatic agent HA oractive pharmaceutical ingredient API within 48 hours. In someembodiments, the polymer is configured to release 80% and about 100% ofhemostatic agent HA or active pharmaceutical ingredient API within 24hours.

In some embodiments, the polymer is configured to release no more than60% of hemostatic agent HA or active pharmaceutical ingredient APIwithin 24 hours. In some embodiments, the polymer is configured torelease no more than 90% of hemostatic agent HA or active pharmaceuticalingredient API after 60 hours. In some embodiments, the polymer isconfigured to release no more than 50% of hemostatic agent HA or activepharmaceutical ingredient API within 12 hours. In some embodiments, thepolymer is configured to release between about 40% and about 90% ofhemostatic agent HA or active pharmaceutical ingredient API between 12and 24 hours. In some embodiments, the polymer is configured to releasebetween about 60% and about 100% of hemostatic agent HA or activepharmaceutical ingredient API between 24 and 36 hours. In someembodiments, the polymer is configured to release between about 65% andabout 100% of hemostatic agent HA or active pharmaceutical ingredientAPI between 36 and 48 hours. In some embodiments, the polymer isconfigured to release between about 70% and about 100% of hemostaticagent HA or active pharmaceutical ingredient API between 48 and 60hours.

Substrate 22 may be coated with single or multiple coating layers of thepolymer, depending on, for example, the amount of hemostatic agent HA oractive pharmaceutical ingredient API to be delivered and desired releaserate. Each layer of the polymer may contain the same or differentamounts of hemostatic agent HA or active pharmaceutical ingredient API.For example, a first layer of the polymer may contain hemostatic agentHA or active pharmaceutical ingredient API, while the second layer ofthe polymer contains either no hemostatic agent HA or activepharmaceutical ingredient API or a lower concentration of hemostaticagent HA or active pharmaceutical ingredient API. As another example, afirst layer of the polymer may comprise hemostatic agent HA or activepharmaceutical ingredient API in a first polymer, while the second layerof the polymer comprises hemostatic agent HA or active pharmaceuticalingredient API in a second polymer that is different than the firstpolymer.

In some embodiments, as shown in FIGS. 22-24, anchorage device 20 is aplanar sheet. In some embodiments, a first polymer can be applied to topsurface 32 and a second polymer can be applied to bottom surface 34. Insome embodiments, the first and second polymers are different polymers.In some embodiments, the first and second polymers release hemostaticagent HA or active pharmaceutical ingredient API at different ratesand/or over different lengths of time. In some embodiments, the firstand second polymers are different polymers, and the first polymerincludes a first amount of hemostatic agent HA or active pharmaceuticalingredient API and the second polymer includes a second amount ofhemostatic agent HA or active pharmaceutical ingredient API, the firstamount being different than the second amount. In some embodiments, thefirst and second polymers are the same polymer, wherein the firstpolymer includes a first amount of hemostatic agent HA or activepharmaceutical ingredient API and the second polymer includes a secondamount of hemostatic agent HA or active pharmaceutical ingredient API,the first amount being different than the second amount.

In some embodiments, shown in FIGS. 25 and 26, substrate 22 is a pocketor envelope in which an implantable medical device can be at leastpartially disposed. That is, substrate 22 is a pouch, bag, covering,shell, or receptacle. For example, substrate 22 can include a firstpiece 22 a and a second piece 22 b that is joined with first piece 22 a.First and second pieces 22 a, 22 b are joined to form the pocket orenvelope. In some embodiments, first and second pieces 22 a, 22 b arejoined along three sides of the pocket or envelope to form a cavity C.First and second pieces 22 a, 22 b are not joined at a fourth side ofthe pocket or envelope to define an opening O such that an implantablemedical device can be inserted through opening O and into cavity C toenclose, encase or surround all or a portion of the implantable medicaldevice within cavity C. In some embodiments, first and second pieces 22a, 22 b are joined with one another along three sides of the pocket orenvelope by heat, ultrasonically, bonding, knitting, or adhesive. Insome embodiment, the pocket or envelope is monolithically formed bymolding the pocket or envelope or producing the pocket or envelope by 3Dprinting, for example.

In some embodiments, anchorage device 20 includes one or a plurality ofarms, such as, for example, extensions 22 c that extend outwardly fromthe pocket formed by first and second pieces 22 a, 22 b, as shown inFIG. 27. In some embodiments, extensions 22 c are spaced apart from oneanother and/or are positioned radially about the pocket. In someembodiments, at least one of extensions 22 c includes one or a pluralityof openings 23 that extends through a thickness of extension 22 c.Openings 23 are spaced apart along a length of extension 23. In someembodiments, openings 23 each have the same width or diameter. In someembodiments, openings 23 each have an oval or oblong shape. Extensions22 c are configured to be coupled to tissue when anchorage device 20 isinserted into an area, such as, for example, a body cavity to secure animplantable medical device within the pocket to the body. In someembodiments, at least one of extensions 22 c is made from abiodegradable and/or resorbable material. In some embodiments, at leastone of extensions 22 c is made from a biodegradable and/or resorbablematerial that degrades and/or resorbs at a faster rate than the pocketsuch that the pocket with the implantable medical device within thepocket remains after extensions 22 c degrade and/or resorb. In someembodiments, at least one of extensions 23 is made from a single layerof material to allow extensions to degrade and/or resorb at a fasterrate than the pocket, which is formed from two layers of material (e.g.,first and second pieces 22 a, 22 b). In some embodiments, extensions 22c and first and second pieces 22 a, 22 b are made from the samematerial. In some embodiments, extensions 22 c and first and secondpieces 22 a, 22 b are made different materials. In some embodiments, atleast one of extensions 22 c is made from a first material and at leastone of extensions 22 c is made from a second material that is differentthan the first material. The first and second materials may include anyof the materials discussed herein. In some embodiments, at least one ofextensions 22 c is made from a hemostatic material. In some embodiments,at least one of extensions 22 c has a hemostatic agents, such as, forexample, one or more of the hemostatic agents discussed herein, appliedto extensions 22 c. The hemostatic agent may be applied to extensions 22c in the same manner the hemostatic agents discussed herein are appliedto substrate 22. In some embodiments, extensions 22 c each have the sameamount of the hemostatic agent. In some embodiments, at least one ofextensions 22 c has a first amount of the hemostatic agent and at leastone of extensions 22 c has a second amount of the hemostatic agent thatis different than the first amount. In some embodiments, at least one ofextensions 22 c includes a first hemostatic agent and at least one ofextensions 22 c includes a second hemostatic agent that is differentthan the first hemostatic agent. In some embodiments, at least one ofextensions 22 c includes an active pharmaceutical ingredient, such as,for example, one or more of the active pharmaceutical ingredientsdiscussed herein, in addition to in in place of the hemostatic agent. Insome embodiments, at least one of extensions 22 c may be cut orotherwise severed from the pocket before or after anchorage device isimplanted within a patient. In some embodiments, at least one ofextensions 22 c is scored to facilitate the removal of extensions 22 cfrom the pocket. This allows a medical practitioner to customizeanchorage device 20 such that anchorage device only includes the amountof extensions 22 c required to secure anchorage device 20 within apatient. That is, any extraneous extensions 22 c can be removed prior toor after implantation of anchorage device 20.

In some embodiments, first and second pieces 22 a, 22 b are portions ofa single sheet that is bent to produce a fold at one end of the pocketor envelope. First and second pieces 22 a, 22 b are joined along sidesof the pocket or envelope that extend transverse to the fold such thatthe fold and the sides of the pocket or envelope do not have anyopenings. First and second pieces 22 a, 22 b are not joined at an end ofthe pocket or envelope opposite the fold to define an opening at the endsuch that a medical device can be inserted through the opening and intoa cavity defined by inner surfaces of first and second pieces 22 a, 22b.

In some embodiments, first and second pieces 22 a, 22 b each include amesh discussed herein. In some embodiments, first piece 22 a includes amesh including pores having a first size and second piece 22 b includesa mesh including pores having a second size, wherein the first size isdifferent than the first size. In some embodiments, the first size isgreater than the second size. In some embodiments, the first size isless than the second size. In some embodiments, first and second pieces22 a, 22 b each include a thin walled structure discussed herein. Insome embodiments one of first and second pieces 22 a, 22 b includes amesh discussed herein and the other one of first and second pieces 22 a,22 b includes a thin walled structure discussed herein that does nothave any pores or apertures.

In some embodiments, first and second pieces 22 a, 22 b are formed fromthe same material. In some embodiments one of first and second pieces 22a, 22 b is formed from a first material, such as, for example, one ofthe materials discussed herein, and the other one of first and secondpieces 22 a, 22 b is made from a second material, such as, for example,one of the materials discussed herein, wherein the second material isdifferent than the first material. For example, first piece 22 a may beformed from a biodegradable and/or bioresorbable material and secondpiece 22 b may be formed from a non-biodegradable and/ornon-bioresorbable material, or vice versa. In some embodiments, firstand second pieces 22 a, 22 b are each formed from a biodegradable and/orbioresorbable material, wherein the biodegradable and/or bioresorbablematerials degrade and/or resorb at the same rate. In some embodiments,first and second pieces 22 a, 22 b are formed from differentbiodegradable and/or bioresorbable materials, wherein one of thebiodegradable and/or bioresorbable materials degrades and/or resorbsmore quickly than the other biodegradable and/or bioresorbable material.

In some embodiments, first and second pieces 22 a, 22 b each include asingle layer of material, such as, for example, one of the materialsdiscussed herein. In some embodiments, at least one of first and secondpieces 22 a, 22 b includes multiple layers. In some embodiments, themultiple layers include more than one layer of the mesh discussedherein. In some embodiments, the multiple layers include more than onelayer of the thin walled structure discussed herein. In someembodiments, the multiple layers include one or more layer of the meshdiscussed herein and one or more layer of the thin walled structurediscussed herein. In some embodiments, the multiple layers include oneor more layer of the mesh discussed herein and one or more layer of thethin walled structure discussed herein, wherein one of the layers ofmesh is positioned between two layers of the thin walled structure. Insome embodiments, the multiple layers include one or more layer of themesh discussed herein and one or more layer of the thin walled structurediscussed herein, wherein one of the layers of thin walled structure ispositioned between two layers of the mesh.

In embodiments discussed herein wherein anchorage device 20 is a pocketor envelope, a first polymer can be applied to first piece 22 a and asecond polymer can be applied to second piece 22 b. In some embodiments,the first and second polymers are different polymers. In someembodiments, the first and second polymers release hemostatic agent HAor active pharmaceutical ingredient API at different rates and/or overdifferent lengths of time. In some embodiments, the first and secondpolymers are different polymers, and the first polymer includes a firstamount of hemostatic agent HA or active pharmaceutical ingredient APIand the second polymer includes a second amount of hemostatic agent HAor active pharmaceutical ingredient API, the first amount beingdifferent than the second amount. In some embodiments, the first andsecond polymers are the same polymer, wherein the first polymer includesa first amount of hemostatic agent HA or active pharmaceuticalingredient API and the second polymer includes a second amount ofhemostatic agent HA or active pharmaceutical ingredient API, the firstamount being different than the second amount. In some embodiments, afirst polymer is applied to the outer surfaces of first and secondpieces 22 a, 22 b and a second polymer is applied to the inner surfacesof first and second pieces 22 a, 22 b, wherein the first polymerincludes a first amount of hemostatic agent HA or active pharmaceuticalingredient API and the second polymer includes a second amount ofhemostatic agent HA or active pharmaceutical ingredient API, the firstamount being different than the second amount. In some embodiments, thefirst amount is more than the second amount. In some embodiments, thefirst amount is less than the second amount.

In some embodiments, anchorage device 20 includes a hydrophiliccomponent, such as, for example, PEG and a crosslinking agent that isapplied to substrate 22. The hydrophilic component and the crosslinkingagent form a hydrogel that absorbs blood and reduces bleeding when incontact with blood or tissue fluid. In some embodiments, the hydrophiliccomponent and the crosslinking agent are sprayed directly onto substrate22. In some embodiments, the hydrophilic component and the crosslinkingagent are provided in a polymer, such as, for example, one or more ofthe polymers discussed herein, and the polymer is applied directly ontosubstrate 22. In some embodiments, the hydrophilic component and thecrosslinking agent are provided in a patch, such as, for example, theVeriset™ haemostatic patch available from Medtronic, Inc., and the patchis applied directly onto substrate 22. In some embodiments, the patchcomprises a plurality of layers. For example, a first layer of the patchcan include a hemostatic agent, such as, for example, oxidizedregenerated cellulose and/or one or more of the hemostatic agentsdiscussed herein. A second layer of the patch can include a crosslinkingagent, such as, for example, trilysine and/or one or more of thecrosslinking agents discussed herein. A third layer of the patch caninclude a hydrophilic agent, such as, for example, PEG and/or one ormore of the hydrophilic agents discussed herein. The second layer of thepatch is positioned between the first and third layers of the patch.

In some embodiments, the hydrophilic component comprises thermogellinghydrogels, PEG-PLGA copolymers, PEG-Poly(N-isopropyl acrylamide),Pluronic (PEO-PPO-PEO triblock), PEG-PCL polymers, PEG-based amphiphiliccopolymers modified by anionic weak polyelectrolytes, (such aspolyacrylic acid, polyglutamic acid) and polymers containing sulfonamidegroups), PEG-based amphiphilic copolymers modified by cationic weakpolyelectrolytes (such as poly (2-vinyl pyridine), Poly(beta-aminoesters), poly (2-(dimethylamino)ethyl methacrylate), multiarm PEGderivatives such as those available from JenKem technology, multiarmedblock and graft PLA copolymers with PEG, PEG with stereo complexedpoly(lactide), acrylated polymers (such as Polyvinylalcohol, dextran,Polyvinylpyrollidone, chitosan, alginate, hyaluronic acid), andcombinations thereof. In some embodiments, the crosslinking agentcomprises one or more agents that induce polymerization of vinyl groupsusing various initiators, light or redox reactions, or by reactions suchas Schiff base formation, Michael type additions, peptide ligation,clock chemistry of functional groups present; one or more agents thatinduce crosslinking by enzymatic reaction (transglutaminase mediatedreaction between carboxamide and amine on proteins),stereo-complexation, metal chelation (alginates using calciumCal2),thermogelation, self-assembly (formation of super helices from proteinchains) inclusion complexation (using cyclodextrin); and combinationsthereof.

Methods

In some embodiments, an anchorage device, such as, for example,anchorage device 20 and a medical device, such as, for example, one ofthe implantable medical devices discussed herein are implanted into abody of a patient. The anchorage device releases a hemostatic agent oractive pharmaceutical ingredient, such as, for example, hemostatic agentHA or active pharmaceutical ingredient API, to reduce or preventbleeding within the patient or treat one of the conditions as discussedherein. In some embodiments, the anchorage device is implanted withinthe patient without the medical device and the medical device is coupledto or inserted into the anchorage device after the anchorage device isimplanted. In some embodiments, the medical device is coupled to orinserted into the anchorage device before the anchorage device isimplanted within the patient and the anchorage device and the medicaldevice are implanted within the patient together.

In some embodiments, the implantable medical device is removed from thepatient after the treatment is completed. In some embodiments, theanchorage device remains implanted within the patient after theimplantable medical device is removed. In some embodiments, theanchorage device is removed from the patient after the implantablemedical device is removed. To remove the anchorage device, tissue thatis ingrown within the substrate of the anchorage device can be cut orotherwise detached from the substrate. In some embodiments, a portion ofthe anchorage device may not be removable from the tissue and willremain implanted within the patient.

In some embodiments, the method includes making a customized anchoragedevice, wherein a hemostatic agent or active pharmaceutical ingredientis selectively applied to the anchorage device to position thehemostatic agent or active pharmaceutical ingredient such that thehemostatic agent is targeted to a location of blood loss in a patientwhen the anchorage device is implanted within the patient or such thatactive pharmaceutical ingredient is targeted to a location to treat atleast one condition when the anchorage device is implanted within thepatient. As such, the method includes identifying a location within thepatient that has a certain condition, such as, for example, infection,scarring and/or infection, or a location where blood lose is occurringor is likely to occur. The medical practitioner than may select aportion or portions of the substrate to which hemostatic agent or activepharmaceutical ingredient should be applied so that the hemostatic agentor active pharmaceutical ingredient is positioned at or adjacent to thelocation within the patient when the anchorage device is implantedwithin the patient. In some embodiments, the method further includesapplying the hemostatic agent or active pharmaceutical ingredient to thesubstrate at the selected portion or portions of the substrate. Forexample, in one embodiment, the method includes loading data into acomputer regarding the selected portion or portions of the substrate andusing a 3D printer that is connected to the computer to print thehemostatic agent or active pharmaceutical ingredient onto the selectedportion or portions of the substrate. It is envisioned that the medicalpractitioner may also select the amount of the hemostatic agent oractive pharmaceutical ingredient that is applied to the portion orportions of the substrate. For example, the medical practitioner canchoose to apply more of the hemostatic agent or active pharmaceuticalingredient to one portion of the substrate than another portion of thesubstrate. This information can be input into the computer such that the3D printer prints the selected amounts of the hemostatic agent or activepharmaceutical ingredient on the portion or portions of the substrate.In some embodiments, the medical practitioner may choose to apply moreof the hemostatic agent or active pharmaceutical ingredient on oneportion of the substrate than another portion of the substrate or thesame amount of the hemostatic agent or active pharmaceutical ingredienton each portion of the substrate. It is envisioned that the anchoragedevice with the hemostatic agent or active pharmaceutical ingredientapplied to the selected portion or portions of the substrate in theselected amounts can be made in a manufacturing facility, in a hospital,or in an operating room. In some embodiments, the process of making theanchorage device may include starting with a blank substrate and thenapplying the hemostatic agent or active pharmaceutical ingredient to theblank substrate in the manner discussed above. In some embodiments, theprocess of making the anchorage device includes forming the substrateand applying the hemostatic agent or active pharmaceutical ingredient tothe substrate. In some embodiments, the process of making the anchoragedevice includes forming the substrate with the hemostatic agent oractive pharmaceutical ingredient applied to the substratesimultaneously. For example, a medical practitioner can input into acomputer the type of substrate desired (size, shape, material, etc.) theportions of the substrate that should include the hemostatic agent oractive pharmaceutical ingredient, and the amounts of the hemostaticagent or active pharmaceutical ingredient to be included in each of theportions. A 3D printer that is connected to the computer can then printthe substrate with the hemostatic agent or active pharmaceuticalingredient on the substrate at the selected portions and in the selectedamounts.

Kits

In some embodiments, kits are provided that include one or a pluralityof anchorage devices, such as, for example, anchorage devices 20. It iscontemplated that each of the anchorage devices included can have adifferent configuration. In some embodiments, the anchorage devices caninclude different hemostatic agents, such as, for example, hemostaticagent HA and/or different active pharmaceutical ingredients, such as,for example, different active pharmaceutical ingredients API. In someembodiments, the anchorage devices can include the hemostatic agent oractive pharmaceutical ingredient located at different portions of thesubstrate. In some embodiments, the anchorage devices can includedifferent amounts of a hemostatic agent or active pharmaceuticalingredient. In some embodiments, the anchorage devices can includedifferent sizes. In some embodiments, the anchorage devices can includedifferent shapes. In some embodiments, the anchorage devices can includedifferent anchorage devices that are designed for use with differentmedical devices, such as, for example, the implantable ornon-implantable medical devices discussed herein. In some embodiments,the kits include one or a plurality of medical devices, such as, forexample, the implantable or non-implantable medical devices discussedherein. In some embodiments, the kit includes instructions for use. Insome embodiments, the kit includes items that are used to make theanchorage devices, such as, for example, the materials used to make thesubstrate, the hemostatic agent(s), the active pharmaceuticalingredient(s), a computer with a processor capable of receiving data andcommunicating with a 3D printer to create an anchorage device having theparameters that were input into the computer (e.g., size, shape,material, agents/ingredients on selected areas of the substrate inselected amounts) and a 3D printer capable of making the anchoragedevice based upon data that is input into the computer regarding theparameters of the implant.

EXAMPLE 1

In one example, an anchorage device having a substrate, such as, forexample, one of the substrates discussed above was prepared. 5 g ofChitosan (HMW, Sigma MKBP1333V) was dissolved in a mixture of 460 mLdistilled water and 40 mL 1M HCl. 10 mL of the viscous solution waspoured into a Teflon petri dish and placed in a hood. After 24 h, thecomposition was dry to touch. It was then placed in a 50° C. oven undervacuum for 24 h. An equivalent procedure was used to prepare substratesfrom other materials. Details are given in Table A below.

TABLE A # Agent Supplier Lot # Weight Solvent Result 1 Chitosan Sigma   5 g 460 mL water + Continuous MKBP1333V 40 mL 1M HCl film 2 PEG 20KFluka,  12.5 g 25 mL No film 1303367 Dichlorome- thane 3 Polyvinyl- ISP   5 g 15 mL water + Film pyrollidone Technologies, 2 mL 1M HCl (PVP)0550149110 4 Jello Sugar Free 0.350 g 5 mL water Film strawberry flavor5 PEG 20K + 1:1 mix of 1 and 5 No Film Jello

EXAMPLE 2

In another example, a hemostatic coated mesh substrate was prepared. Aknitted multifilament mesh was taped down on a flat Teflon sheet.Prepared hemostat solutions described above were poured onto the meshand spread using a Gardner Knife. The compositions were allowed to dryovernight in the hood and then at 50° C. under vacuum for 24 hours.Chitosan and PVP solutions and a 1:1 mixture of Chitosan and PVP wereused to prepare hemostat coated meshes.

Hemostatic properties of the anchorage devices prepared in Examples 1and 2 were observed. Water absorption was used as the initial screeningtest for hemostatic properties. A commercial hemostat Surgifoam was usedas the control. Not wetted Surgifoam does not soak water easily, butwetted one works as a sponge. A piece of the hemostatic composition wasplaced on a flat Teflon surface. 3 drops of water were placed in thecenter of the composition and the time for water to absorb and thephysical state of the hemostats were observed. Results are shown in FIG.29.

EXAMPLE 3

In another example, an anchorage device was prepared wherein theanchorage device had an active pharmaceutical ingredients, such as, forexample, at least one antimicrobial agent was applied to a substrate,such as for example, a hemostatic mesh. A sheet of organic regeneratedcellulose (ORC) made from multifilament fibers was stretched over arectangular frame (10 inches×13 inches). This was coated with a 4%Weight by volume solution containing Rifampin, minocycline and tyrosinepolyarylate (15:15:70 by weight) dissolved in THF:Methanol (9:1 VN)using an ultrasonic spraying machine (Ultrasonic Systems, Inc.,Haverhill, Mass.). The coated mesh was dried under vacuum for 24 h at 50C.

EXAMPLE 4

In another example, an agent, such as, for example, at least one of theactive pharmaceuticals discussed herein was selectively applied to asubstrate of an anchorage device. Different patterns were created on anORC sheet (made from multifilament fibers) by masking predeterminedareas of the mesh with masking tape. The patterned sheet of ORC wasstretched over a rectangular frame (10 inches×13 inches). This wascoated with a 4% Weight by volume solution containing Rifampin,minocycline and tyrosine polyarylate (15:15:70 by weight) dissolved inTHF:Methanol (9:1 VN) using an ultrasonic spraying machine (UltrasonicSystems, Inc., Haverhill, Mass.). The coated mesh was dried under vacuumfor 24 h at 50 C. The masking tape was peeled off to create meshes withthe predetermined pattern.

EXAMPLE 5

In another example, an anchorage device having a configuration of apocket, pouch or envelope discussed above was prepared. Two sheets ofthe coated synthetic mesh were coated mesh placed one on top of theother and sealed and cut into the shape using an ultrasonic weld. Theanvil used in the ultrasonic welding resulted in the formation of apouch 2.5″×2.75″ in size, sealed on approximately 3 and one-half sides.By changing the size and shape of the anvil, pouches of different sizesand shapes can be made.

EXAMPLE 6

In another example, an agent, such as, for example, at least one of thehemostatic agents discussed herein was prepared to be applied to asubstrate of an anchorage device, such as, for example, one of thesubstrates discussed herein. A 5% solution of chitosan (Aldrich, lowmolecular weight) was prepared as follows. 5 g of chitosan, 2.5 g ofsuccinic acid were added to 100 mL of distilled water in a 250 mL glassjar containing a magnetic stir bar. The mixture was stirred at 500 rpmuntil a clear viscous solution was obtained.

EXAMPLE 7

In another example, an agent, such as, for example, at least one of thehemostatic agents discussed herein was applied to a substrate of ananchorage device, such as, for example, one of the pockets, pouches orenvelopes discussed herein. A piece of Tyvek (blown PTFE) film (sizeequal to that of the inner dimensions of the envelope) was placed withinthe envelope. The envelope was placed on a flat sheet of Teflon. About10 mL of the hemostat solution was poured on the envelope and spreadusing a polypropylene rod. After drying for 24 hours under the hood, theenvelope was removed, excess hemostat was trimmed off and the innerTeflon sleeve was removed. This resulted in the hemostatic agent beingapplied to one side of the envelope. That is, the other side of theenvelope did not include the hemostatic agent.

EXAMPLE 8

In another example, an agent, such as, for example, at least one of thehemostatic agents discussed herein was applied to a substrate of ananchorage device, such as, for example, one of the pockets, pouches orenvelopes discussed herein. The envelope was mounted on a plasticmandrel, which was then dipped into the viscous solution of hemostat.Excess solution was allowed to drain. The mandrel was dried under vacuumat 80 C for 36 hours. After cooling, the envelope was removed from themandrel. This resulted in the hemostatic agent being applied to bothsides of the envelope.

EXAMPLE 9

In another example, an anchorage device having a configuration of apocket, pouch or envelope discussed above was prepared. The envelopeswere made from one or more sheets comprising a hemostatic agent and amesh material that is coated with an antibiotic, such as, for example atleast one of the antibiotics discussed herein. The devices may becreated from hemostatic sheets and synthetic mesh by fusing them usingheat, ultrasonic energy or solvent, polymeric solutions or glue, asdiscussed below.

Heat

1. In one example, two sheets of ORC mesh coated with tyrosine polymerplus Rifampin and Minocycline were placed within the jaws of a PACWORLDbar sealer (using the following conditions: 7 Sec, 140 C, 80 psi. Thesheets were fused together, as discussed herein, and shown in FIG. 30.

2. In one example, one sheet of ORC mesh coated with tyrosine polymer,Rifampin and Minocycline and one sheet of biodegradable mesh made fromglycolide, caprolactone and trimethylene carbonate coated with tyrosinepolymer with Rifampin and Minocycline were placed within the jaws of aPACWORLD bar sealer (using the following conditions: 7 Sec, 140 C, 80psi. The sheets were fused together, as discussed herein and shown inFIG. 31.

3. In one example, one sheet of uncoated ORC mesh and one sheet ofbiodegradable mesh made from glycolide, caprolactone and trimethylenecarbonate coated with tyrosine polymer with Rifampin and Minocyclinewere placed within the jaws of a PACWORLD bar sealer (using thefollowing conditions: 7 Sec, 140 C, 80 psi. The sheets were fusedtogether, as discussed herein and shown in FIG. 32.

4. In one example, one sheet of coated ORC mesh coated with tyrosinepolymer plus Rifampin and Minocycline in a pattern and one sheet ofbiodegradable mesh made from glycolide, caprolactone and trimethylenecarbonate coated with tyrosine polymer with Rifampin and Minocycline ina pattern were placed within the jaws of a PACWORLD bar sealer (usingthe following conditions: 7 Sec, 140 C, 80 psi. The sheets were fusedtogether, as discussed herein. The pattern on the ORC mesh sheet isshown in FIG. 33.

Solvent Based

5. In one example, a solution of tyrosine polymer was placed between twosheets of uncoated ORC. The sheets were clamped together. After dryingfor 36 h under ambient conditions, it was further dried at 80 C for 24hours. The sheets were fused together, as discussed herein.

6. In one example, two sheets of polymer coated ORC were wetted withDMSO. The sheets were clamped together. After drying for 36 h underambient conditions, it was further dried at 80 C for 24 hours. Thesheets were fused together, as discussed herein.

7. In one example, two sheets of polymer coated ORC was wetted with DMF.The sheets were clamped together. After drying for 36 h under ambientconditions, it was further dried at 80 C for 24 hours. The sheets werefused together, as discussed herein.

Adhesive

8. In one example, a small amount of cyanoacrylate glue was placedbetween two sheets of uncoated ORC. The sheets were clamped together anddried at room temperature for 1 hour. The sheets were fused together, asdiscussed herein.

Sewing

9. In one example, two sheets of ORC mesh coated with tyrosine polymerplus Rifampin and Minocycline were sewn together

10. In one example, one sheet of ORC mesh coated with tyrosine polymer,Rifampin and Minocycline and one sheet of biodegradable mesh made fromglycolide, caprolactone and trimethylene carbonate coated with tyrosinepolymer with Rifampin and Minocycline were sewn together

11. In one example, one sheet of uncoated ORC mesh and one sheet ofbiodegradable mesh made from glycolide, caprolactone and trimethylenecarbonate coated with tyrosine polymer with Rifampin and Minocyclinewere sewn together

12. In one example, one sheet of coated ORC mesh coated with tyrosinepolymer plus Rifampin and Minocycline in a pattern and one sheet ofbiodegradable mesh made from glycolide, caprolactone and trimethylenecarbonate coated with tyrosine polymer with Rifampin and Minocycline ina pattern were sewn together.

13. In one example, one sheet of uncoated ORC mesh and one sheet ofbiodegradable film made from tyrosine polymer with Rifampin andMinocycline were sewn together.

14. In one example, one sheet of ORC mesh coated with tyrosine polymerplus Rifampin and Minocycline and one sheet of biodegradable film madefrom tyrosine polymer with Rifampin and Minocycline were sewn togetherwere sewn together.

EXAMPLE 10

In another example, an agent, such as, for example, at least one of thehemostatic agents discussed herein was selectively applied to asubstrate of an anchorage device. A sheet of biodegradable mesh madefrom glycolide, caprolactone and trimethylene carbonate coated withtyrosine polymer with Rifampin and Minocycline was fixed to a flatsurface. Drops of a solution of Chitosan (5% w/v) in water containingsuccinic acid was applied to the mesh using a syringe. The mesh wasdried overnight at room temperature and then at 80° C. under vacuum for24 h.

EXAMPLE 11

In another example, agents, such as, for example, at least one of thehemostatic agents discussed herein and at least one of the activepharmaceutical ingredients discussed herein were selectively applied toa substrate of an anchorage device. A 4% Weight by volume solutioncontaining Rifampin, minocycline and tyrosine polyarylate (15:15:70 byweight) dissolved in THF:Methanol (9:1 VN) was first prepared. Fineparticles of a suitable hemostatic agent was suspended in this mixtureand the suspension was sprayed onto a suitable mesh substrate. Afterdrying under ambient condition until the coating was dry to the touch,the mesh was dried in a vacuum oven at 80° C. for 24 to 72 hours. Thehemostatic agents can be selected from any of the hemostatic agentsdiscussed herein and/or tranexamic acid, amino caproic acid (e.g.,epsilon amino caproic acid), aprotinin, natural serine proteaseinhibitors, or polymers such as ORC or chitosan or otherpolysaccharides. In some embodiments, the hemostatic agents can includeArista AH hemostat and a desiccant. In some embodiments, the Arista AHhemostat is a hydrophilic, flowable, sterile, fine, dry white powdermade by crosslinking purified plant starch through a proprietary processinto Microporous Polysaccharide Hemospheres (MPH). In some embodiments,the hemostatic agents can include those discussed by Barnard J, MillnerR, “A Review of Topical Hemostatic Agents for Use in Cardiac Surgery,”Ann Thorac Surg. 2009, 88: 1377-1383. 10.1016, which is incorporatedherein by reference, in its entirety. In some embodiments, thehemostatic agents can include those discussed by Jill Henley, Jerry D.Brewer, “Newer Hemostatic Agents Used in the Practice of DermatologicSurgery,” Dermatology Research and Practice 2013, 1-15, which isincorporated herein by reference, in its entirety. In some embodiments,the hemostatic agents can include those discussed by F. I. Broekema, W.Van Oeveren, J. Zuidema, S. H. Visscher, and R. R. M. Bos, “In vitroanalysis of polyurethane foam as a topical hemostatic agent,” Journal ofMaterials Science, vol. 22, no. 4, pp. 1081-1086, 2011, which isincorporated herein by reference, in its entirety.

EXAMPLE 12

In another example, anchorage devices having a substrate, such as, forexample, one of the substrates discussed above were prepared wherein thesubstrate was made from fibers that include a hemostatic agent, such as,for example, at least one of the hemostatic agents discussed herein, andfibers that do not include a hemostatic agent. In one example, thefibers that include the hemostatic agent are made from an aqueoussolution that include the hemostatic agent(s). In some embodiments, anactive pharmaceutical ingredient is added to the aqueous solution. Inone example, the fibers that do not include the hemostatic agent arecoextruded with an active pharmaceutical ingredient, such as, forexample, at least one of the active pharmaceutical ingredients discussedherein. The fibers are swelled in some solvent containing the API, suchas, for example, polyurethane or silicone in THF. The fibers thatinclude the hemostatic agent and the fibers that do not include thehemostatic agent are dried, and the dried fibers are used to form amesh. In some embodiments, the fibers that include the hemostatic agentare made as discussed by Pillai, C. K. S.; Paul, W.; Sharma, C. P.Chitin and chitosan polymers: Chemistry, solubility and fiber formation.Prog. Polym. Sci. 2009, 34, 641-678, which is incorporated herein byreference, in its entirety.

EXAMPLE 13

In another example, an agent, such as, for example, at least one of theactive pharmaceuticals discussed herein was applied to a substrate of ananchorage device such that the agent eluted or released from thesubstrate at a selected rate. The substrate was made from variouscombinations of Glycoprene®, ORC, polymer-coated Glycoprene® (e.g., oneof the tyrosine-derived polymers discussed herein), and polymer-coatedORC (e.g., one of the tyrosine-derived polymers discussed herein). Thesamples were weighed in 20 mL scintillation vials and then immersed in20 mL of phosphate buffered saline (pH 7.4). The vials were allowed toshake at 120 rpm in an incubator at 37° C. At various subsequent timepoints, 1 mL of the buffer was removed for analysis by UPLC. At eachtime point after 1 mL was removed, the buffer was decanted. The vialswere replenished with fresh buffer and returned to the incubator. Thevolume of fresh buffer was gradually reduced from the initial 20 mL to10 mL, 5 mL, and 2 mL in order to maintain a concentration that can bedetected by UPLC.

Samples of coated ORC and coated Glycoprene® were weighed in 20 mLscintillation vials. Samples were initially dissolved in DMSO andallowed to shake for at least 15 minutes. Then, MeOH was added and vialswere allowed to shake for another minimum of 15 minutes. One (1) mL ofeach solution was then filtered through a 0.45 micron PTFE filter andloaded onto the UPLC for analysis. Results below are reported as acumulative % released against time.

Substrates, such as, for example, the substrates discussed herein, wereprepared, as discussed herein, to include coatings (e.g., polymers) thatelute an active pharmaceutical ingredient, such as, for example, atleast one of the active pharmaceutical ingredients discussed herein, atdifferent rates. Ten samples were produced (Samples 1-6 and 9-12), asshown in FIG. 34. In the data provided below, “Tyrx” or “TYRX” refers toa degradable polymer, and in particular, to one or more of thetyrosine-derived polymers discussed herein, wherein the polymer includesat least one active pharmaceutical ingredient.

The active pharmaceutical ingredient(s) or drug(s) in each of Samples1-6 and 9-12 is shown in FIG. 35. Further details regarding thesubstrates used in Samples 1-6 and 9-12 are provided below.

AIGIS-R refers to a resorbable mesh substrate that is coated with apolymer, such as, for example, one of the tyrosine-derived polymersdiscussed herein, wherein the polymer includes at least one activepharmaceutical ingredient, as shown below. In the samples that includeGlycoprene®, the Glycoprene® is a mesh that forms the substrate. Theelution rates of the active pharmaceutical ingredients in Samples 1-6and 9-12 are shown in the elution profiles in FIGS. 36A-36T.

In this example, different substrates were examined to test and comparethe elution profiles of the different substrates to determine theeffect, if any, of combining polymer-coated substrates with uncoatedsubstrates.

When uncoated Glycoprene® was added to coated ORC in samples 1 and 2,both minocycline and rifampin releases were below 20% after 2 hours. By24 hours, minocycline release was above 60%, and rifampin release wasover 20%. Minocycline and rifampin releases continued to increasebetween 24 and 30 hours.

With the addition of uncoated ORC to coated Glycoprene® in samples 3 and4, more than 20% minocycline and 20% rifampin was released after 2hours. After 6 hours, minocycline release was over 80% while rifampinrelease was over 60%.

Samples 5 and 6 consisted of both coated Glycoprene® and coated ORC.After 2 hours, minocycline release was over 20% while rifampin releasewas around 50%. By 6 hours, more than 60% of minocycline was released,and more than 20% of rifampin was released. After 24 hours, rifampinrelease was approximately 40% while minocycline release was over 70%.Minocycline and rifampin releases continued to increase between 24 and30 hours.

Minocycline and rifampin elution from samples 9 and 10 (coated ORC) wasbelow 20% after 2 hours. After 24 hours, minocycline release was over60%, while rifampin release was over 20%. Minocycline and rifampinreleases continued to increase between 24 and 30 hours.

For samples 11 and 12 of coated Glycoprene®, more than 80% minocyclineand more than 60% rifampin was released in 2 hours. Minocycline andrifampin release rate gradually increased until it leveled off after 6hours.

In samples 1-6 and 9-10 after 2 hours immersion in PBS, the ORCcomponent can be visually observed to be swollen.

EXAMPLE 14

To determine the stability of active pharmaceutical ingredients, suchas, for example, one or more of active pharmaceutical ingredients 26when combined with a hemostatic agent, such as, for example, one or moreof hemostatic agents 24, mixtures of rifampin and minocycline wereprepared in phosphate-buffered saline (PBS) with and without tranexamicacid (TXA). The mixtures were tested both at room temperature (RT)(about 23° C.) and at 37° C. As shown in FIG. 37, mixtures of rifampinand minocycline in PBS with and without tranexamic acid havesubstantially the same percentage area of rifampin and minocycline, thusindicating that tranexamic acid does not negatively affect the stabilityof rifampin and minocycline. In particular, the percentage area ofrifampin was substantially the same for mixtures of rifampin andminocycline in PBS with and without tranexamic acid, regardless of thetemperature; the percentage area minocycline was substantially the samefor mixtures of rifampin and minocycline in PBS with and withouttranexamic acid when the mixtures were at the same temperature.

EXAMPLE 15

To determine the elution of active pharmaceutical ingredients, such as,for example, one or more of active pharmaceutical ingredients 26 from apolymer, such as, for example, one of the polymers discussed herein, invitro when the active pharmaceutical ingredients are combined with ahemostatic agent, such as, for example, one or more of hemostatic agents24, in vitro elution of rifampin and minocycline from polymers in thep22-27.5 family containing different amounts of tranexamic acid wasevaluated in a PBS buffer over 25 hours. B1=PBS pH 7.4; B2=PBS, pH7.4+TXA (0.05 mg/mL); B3=PBS, pH 7.4+TXA (5 mg/mL). The elution ratesfor rifampin and minocycline are shown in FIG. 38. As shown in FIG. 38,the elution rates of rifampin and minocycline were not effected by thepresence of TXA in the release media.

EXAMPLE 16

To determine the sustained release of active pharmaceutical ingredients,such as, for example, one or more of active pharmaceutical ingredients26 from a polymer, such as, for example, one of the polymers discussedherein, when the active pharmaceutical ingredients are combined with ahemostatic agent, such as, for example, one or more of hemostatic agents24, thin and thick solvent cast films containing rifampin (Rif) andtranexamic acid were prepared. Thin and thick solvent cast filmscontaining minocycline (Min) and tranexamic acid were also prepared. Thetranexamic acid phase was separated in each of the films. Thin films hada thickness of about 30 microns and thick films had a thickness of about400 microns. Elution of rifampin and minocycline was measured over about30 hours. The percentage of rifampin and minocycline released at 2hours, 6 hours and 24 hours was recorded. As shown in FIG. 39, the thinfilms released rifampin and minocycline more quickly than the thickfilms at the same time intervals. However for each set of films (thickand thin), rifampin and minocycline were shown to elute at similarrates.

EXAMPLE 17

Tests were conducted to compare the time required to induce bloodclotting in vitro when different amounts of hemostatic agent isadministered in the presence of TYRX (degradable mesh coated withP22-27.5 containing rifampin and minocycline), as shown in FIG. 40.Clotting time was increased when higher amounts of TXA was present (1.6mg TXA vs 200 mg of TXA), as shown below.

EXAMPLE 18

Tests were conducted to compare the time required for differenthemostatic agents to induce blood clotting in vitro versus the timerequired to induce blood clotting in vitro when no hemostatic agent isadministered. In particular, the time required to induce blood clottingwas plotted for blood alone, a polymer in the p22-xx family(P22-27.5-TYRX), Surgicel, a polymer in the p22-xx family(P22-27.5-TYRX) with 1.6 mg of TXA, 1.2 mg of TXA alone and a polymer inthe p22-xx family (P22-27.5-TYRX) with X mg of TXA. As shown in FIG. 41,blood alone and the p22-27.5 polymer were both effective to induce bloodclotting in about 14 minutes; Surgicel was effective to induce bloodclotting in about 17 minutes; the p22-27.5 polymer having 1.6 mg of TXAwas effective to induce blood clotting in about 12 minutes; 1.2 mg ofTXA alone was effective to induce blood clotting in about 19 minutes;and the p22-27.5 polymer having X mg of TXA was effective to induceblood clotting in about 32 minutes, thus indicating that the p22-xxpolymer may induce blood clotting better than blood alone, the p22-27.5polymer alone, and TXA alone.

Tests were conducted to compare the time required for differenthemostatic agents to induce blood clotting in vitro versus the timerequired to induce blood clotting in vitro when no hemostatic agent isadministered. In particular, the time required to induce blood clottingwas plotted for blood alone, TYRX, Surgicel, TYRX with 1.6 mg of TXA,1.2 mg of TXA alone and TYRX with 200 mg of TXA. In this example, TYRXrefers to a Glycoprene mesh that is coated with P22-27.5 (a polymer inthe P22-X family) containing Rifampin and Minocycline. As shown in FIG.41, blood alone and TYRX were both effective to induce blood clotting inabout 14 minutes; Surgicel was effective to induce blood clotting inabout 17 minutes; TYRX with 1.6 mg of TXA was effective to induce bloodclotting in about 12 minutes; 1.2 mg of TXA alone was effective toinduce blood clotting in about 19 minutes; and the p22-27.5 polymerhaving 200 mg of TXA was effective to induce blood clotting in about 32minutes, thus indicating that TYRX with low amount of TXA (1.6 mg) mayinduce blood clotting better than TYRX with 200 mg TXA.

EXAMPLE 19

To determine the impact, if any, of a hemostatic agent, such as, forexample, one or more of hemostatic agents 24 on bacterial attachment,three samples were prepared. The first sample included a TYRX polymer inthe p22-xx family (P22-27.5-TYRX); the second sample included TYRX andtranexamic acid (TYRX+TXA); and the third sample included anextracellular matrix (ECM) to be used as a control. In this example,TYRX refers to a glycoprene mesh that is coated with P22-27.5 (a polymerin the P22-X family) containing rifampin and minocylcline. The sampleswere each suspended in 3 mL of a Brain Heart Infusion (BHI) medium at37° C. for 24 hours. The samples were each inoculated with 2×ColonyForming Units (CFU)/mL of a clinical strain of Methicillin-resistantStaphylococcus aureus (MRSA). After 24 hours, each of the samples wasrinsed twice and bacterial attachment was visualized by Live/Deadstaining and imaged with Leica DM RXE microscope attached to a TCS SP2AOBS confocal system (Leica Microsystems, Exton, Pa.). As shown in FIG.42, the TYRX and TYRX+TXA samples exhibited less bacterial attachmentthan the ECM control.

EXAMPLE 20 Chitosan Solutions for Preparing Films

1 gram of Chitosan (Sigma) was added to 100 mL of Aqueous Acetic acid(1% Acetic acid). The mixture was stirred using a magnetic stir baruntil no solids remained.

Films were cast by pouring on 10 mL of the chitosan solution onto aTEFLON sheet. The solution was covered with a Petridish dried in aventilated hood 24 hrs. The Petridish was removed and the films driedfor an addition 72 hrs. A transparent film was obtained.

50 mg of Tranexamic acid was added to 10 g of the chitosan solutionprepared as described above in a 20-mL scintillation vial. The vial wascapped and placed on a shaker. The contents were shaken for 1 hr, whenall the TXA had dissolved.

Films were cast by pouring on to a TEFLON sheet. The solution wascovered with a Petridish dried in a ventilated hood 24 hrs. ThePetridish was removed and the films dried for an addition 72 hrs. Atransparent film was obtained.

50 mg of Tranexamic acid, 50 mg of Rifampin, 50 mg of Minocycline.HCLwas added to 10 g of the chitosan solution prepared as described abovein a 20-mL scintillation vial. The vial was capped and placed on ashaker. The contents were shaken for 1 hr, when all the drugs had haddissolved.

Films were cast by pouring on to a TEFLON sheet. The solution wascovered with a Petridish dried in a ventilated hood 24 hrs. ThePetridish was removed and the films dried for an addition 72 hrs. Atransparent red film was obtained.

Two kinds of meshes were used in these experiments—a monofilament meshof polypropylene (non-absorbable) and a multifilament absorbable mesh(GLYCOPRENE II), which is made from glycolide, caprolactone andtrimethylene carbonate.

Strips of mesh approximately 1 cm×3 cm were hand dipped into thesolutions of chitosan, Chitosan+Tranexamic acid and Chitosan+Tranexamicacid+Rifampin+Minocycline.HCl. These solutions were prepared asdescribed above. Excess solution was removed using Kim wipes and wetstrips were hung to dry in a hood. The coated meshes were dry to thetouch after overnight drying.

EXAMPLE 21 Avoiding Crystallization in Films

To assess how to avoid crystallization in films, four samples wereprepared—sample J, sample L, sample B2 and sample F2. Sample J includesa polymer in the p22-xx family (P22-27.5-TYRX), rifampin, minocyclineand tranexamic acid. Sample L includes a polymer in the p22-xx family(P22-27.5-TYRX), rifampin, minocycline, tranexamic acid and water.Sample B2 includes a polymer in the p22-xx family (P22-27.5-TYRX) andtranexamic acid. Sample F2 includes a polymer in the p22-xx family(P22-27.5-TYRX), tranexamic acid and water.

The samples were imaged using a digital microscope under a variety ofillumination conditions and magnifications of 50×, 100×, and 200×.Transmitted crossed-polarized illumination highlighted anisotropic,apparently crystalline features in several films, as shown in FIG. 43.

Transmitted crossed-polarized illumination highlighted anisotropic,apparently crystalline features in films containing TXA. However, theapparently crystalline features were not observed in sample F2 or sampleL, as shown in FIG. 43. Both of these samples were made with 1 mLaqueous TXA.

EXAMPLE 22 Preparation of Electrospun Mats

Some of the properties of electro spun fibers are their high surfacearea, inherent 3 dimensional features and tunable porosity. In electrospinning, a thin stream of charged polymer solution is ejected from aspinneret in the presence of a high electric field (in the range of 105to 106 V/m) applied between a conducting collector and the spinneret.Due to the application of electrostatic potential, the jet will stretchand whip around along with solvent evaporation because of the columbicrepulsion between the surface charges. The resulting mass of fine fiber(nanofibers) is then collected on the target electrodes.

This technique can be used to molecules within the fiber matrix. If thedrug is soluble in the polymer solution, then the drugs will behomogeneously distributed (dissolved) within the fiber. If however, thedrug particles are not soluble in the polymer matrix, then the insolubleparticles will be entrapped within the fiber matrix.

This technique can therefore be used to encapsulate water soluble activepharmaceutical ingredients and/or hemostatic agents (such as, forexample tranexamic acid, peptides, proteins) which have poor solubilityin organic solvents. Typically a solution of the organic soluble activepharmaceutical ingredients and/or hemostatic agents with a particle sizeof less than 100 microns are suspended in an organic solution of apolymer and subjected to the electrospinning process, resulting inmatrix of polymer fibers containing particles of drug. This technique isuseful since high payloads of drugs can be incorporated into thesubstrate. The polymer solution may optionally contain other organicsoluble compounds, including active pharmaceutical ingredients and/orhemostatic agents. More than one organic insoluble compound can besuspended in the polymer solution.

For example, the organic solution may be mixture of P22-27.5+Rifampin(10% w/w relative to polymer) and Minocycline (10% w/w relative topolymer) dissolved in a 9:1 mixture of THF: Methanol. 10% of fine powderof TXA (10% W/W relative to polymer) may be suspended in this solutionand subjected to electrospray. The resulting nanoofiber mat wouldtherefore contain 10% each of Rifampin and Minocycline dissolved in thefibers and 10% TXA entrapped between fibers.

It will be understood that various modifications may be made to theembodiments disclosed herein. Therefore, the above description shouldnot be construed as limiting, but merely as exemplification of thevarious embodiments. Those skilled in the art will envision othermodifications within the scope and spirit of the claims appended hereto.

1-20. (canceled)
 21. A hemostatic device comprising: a biodegradablesheet made from a first hemostatic agent; and a second hemostatic agentselectively positioned on the sheet such that the sheet comprises aplurality of first portions that each include the second hemostaticagent and are spaced apart from one another by a second portion of thesheet that does not include the second hemostatic agent.
 22. Thehemostatic device recited in claim 21, wherein the second hemostaticagent is selectively positioned on the sheet such that the secondhemostatic agent is targeted to a location of blood loss of a patient.23. The hemostatic device recited in claim 21, wherein the sheetcomprises opposite top and bottom surfaces, the second hemostatic agentbeing positioned on the bottom surface.
 24. The hemostatic devicerecited in claim 21, wherein the sheet comprises opposite top and bottomsurfaces, the second hemostatic agent being positioned on the bottomsurface and is spaced apart from the top surface.
 25. The hemostaticdevice recited in claim 21, wherein the second hemostatic agent ispositioned about a perimeter of the sheet.
 26. The hemostatic devicerecited in claim 21, wherein the second hemostatic agent is positionedabout an entire perimeter of the sheet and is spaced apart from aninterior portion of the sheet.
 27. The hemostatic device recited inclaim 21, wherein the sheet comprises only one piece.
 28. The hemostaticdevice recited in claim 21, wherein the second hemostatic agent isselectively positioned on one side of the sheet and an activepharmaceutical ingredient is selectively positioned on an oppositesecond side of the sheet, the second side being free of the secondhemostatic agent.
 29. The hemostatic device recited in claim 28, whereinthe active pharmaceutical ingredient is selected from a group consistingof anesthetics, antibiotics, anti-inflammatory agents, procoagulantagents, fibrosis-inhibiting agents, anti-scarring agents, leukotrieneinhibitors/antagonists, cell growth inhibitors and mixtures thereof. 30.The hemostatic device recited in claim 28, wherein the second hemostaticagent is selected from a group consisting of epinephrine, tranexamicacid, chitosan and oxidized regenerated cellulose.
 31. The hemostaticdevice recited in claim 27, wherein the second hemostatic agent isselectively positioned on opposite first and second sides of the sheetand an active pharmaceutical ingredient is selectively positioned on atleast one of the sides of the sheet.
 32. The hemostatic device recitedin claim 27, wherein the sheet comprises a first portion and a secondportion, the second hemostatic agent being selectively positioned on thefirst portion, an active pharmaceutical ingredient being selectivelypositioned on the second portion.
 33. The hemostatic device recited inclaim 32, wherein the active pharmaceutical ingredient is selected fromthe group consisting of rifampin and minocycline and mixtures thereof.34. The hemostatic device recited in claim 21, wherein: the firsthemostatic agent is collagen; and the sheet is made entirely from thefirst hemostatic agent.
 35. The hemostatic device recited in claim 21,further comprising a polymer that is applied to the sheet, the polymercomprising the second hemostatic agent.
 36. The hemostatic devicerecited in claim 35, wherein the polymer is selected from a groupconsisting of polylactic acid, polyglycolic acid, poly(L-lactide),poly(D,L-lactide)polyglycolic acid[polyglycolide],poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide),poly(D,L-lactide-co-glycolide), poly(glycolide-co-trimethylenecarbonate), poly(D,L-lactide-co-caprolactone),poly(glycolide-co-caprolactone), polyethylene oxide, polydioxanone,polypropylene fumarate, poly(ethyl glutamate-co-glutamic acid),poly(tert-butyloxy-carbonylmethyl glutamate), polycaprolactone,polycaprolactone co-butylacrylate, polyhydroxybutyrate, copolymers ofpolyhydroxybutyrate, poly(phosphazene), poly(phosphate ester),poly(amino acid), polydepsipeptides, maleic anhydride copolymers,polyiminocarbonates, poly[(97.5% dimethyl-trimethylenecarbonate)-co-(2.5% trimethylene carbonate)], poly(orthoesters),tyrosine-derived polyarylates, tyrosine-derived polycarbonates,tyrosine-derived polyiminocarbonates, tyrosine-derived polyphosphonates,polyethylene oxide, polyethylene glycol, polyalkylene oxides,hydroxypropylmethylcellulose, polysaccharides, hyaluronic acid,chitosan, regenerate cellulose and mixtures thereof.
 37. A hemostaticdevice comprising: a sheet consisting of a first hemostatic agent, thefirst hemostatic agent being selected from the group consisting ofcollagen, epinephrine, tranexamic acid, chitosan and cellulose; a secondhemostatic agent selectively positioned on the sheet such that thesubstrate comprises a plurality of first portions that each include thesecond hemostatic agent positioned thereon and are spaced apart from oneanother by a second portion of the sheet that does not include thesecond hemostatic agent positioned thereon; and an active pharmaceuticalingredient selectively positioned on the sheet.
 38. The hemostaticdevice recited in claim 37, wherein the active pharmaceutical ingredientis selectively positioned on the sheet such that active pharmaceuticalingredient is targeted to a location to treat at least one conditionwhen the sheet is applied to the patient.
 39. The hemostatic devicerecited in claim 37, wherein the active pharmaceutical ingredient isselectively positioned on the sheet such that active pharmaceuticalingredient is targeted to a location to provide pain relief, inhibitscarring or fibrosis and/or inhibit bacterial growth.
 40. A hemostaticdevice comprising: a sheet consisting of collagen; and tranexamic acid,rifampin and minocycline selectively positioned on the sheet.